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Ribeiro CM, Oliveira SR, Flauzino T, Alfieri DF, Simão ANC, Lozovoy MAB, Maes M, Reiche EMV. The effects of the MTHFR 677C>T (rs1801133) genetic variant on susceptibility and disability worsening in multiple sclerosis patients are mediated by homocysteine. Mult Scler Relat Disord 2024; 91:105883. [PMID: 39270536 DOI: 10.1016/j.msard.2024.105883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/29/2024] [Accepted: 09/07/2024] [Indexed: 09/15/2024]
Abstract
BACKGROUND Interactions between genetic and environmental variables contribute to the autoimmune inflammatory process in multiple sclerosis (MS). Elevated homocysteine levels, and vitamin D, vitamin B12, and folate deficiencies are some of the environmental factors associated with the pathogenesis of MS. Considering that the relationship between MTHFR 677C>T (rs1801133) genetic variant, homocysteine, and folate in patients with MS remains unclear and that their role were not extensively explored in the clinical course of the disease, we investigated whether this variant and plasma homocysteine and folate levels are associated with MS susceptibility, disability, disability progression, and inflammatory biomarkers. METHODS The case-control study included 163 patients with MS categorized using the Expanded Disability Status Scale (EDSS) as mild (EDSS<3) and moderate/high (EDSS≥3) disability, and 226 healthy controls (HC). Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS) and the MTHFR 677C>T variant was genotyped using real time polymerase chain reaction. The plasma levels of some inflammatory biomarkers were determined. Two new composed scores were proposed: the first, namely as inflammatory activity index (IAI), was entered as a latent vector extracted from the macrophage M1 + T helper (Th)1 + Th17 + Th2 + T regulatory (Treg) cytokines, + tumor necrosis factor (TNF)-α+ soluble TNF receptor (sTNFR)-1 + sTNFR2. The second score, namely MS-severity index was entered as a latent vector extracted from the EDSS + MSSS scores + MS diagnosis. RESULTS Patients with MS showed higher homocysteine and folate than controls (p < 0.001); homocysteine, and the M1, Th1, Th17, and Th2 Treg cytokine values were different between the three study groups and increased from HC to MS patients with mild disability and to MS patients with moderate/high disability (p < 0.0001). The levels of TNF-α and their soluble receptors sTNFR1 and sTNFR2 were higher in MS patients with EDSS≥3 than in the two other groups (EDSS<3 and HC) (p < 0.001). There was no association between the MTHFR 677 C > T genotypes and MS susceptibility, disability and disability progression (p > 0.05). Moreover, 21.8 % of the disability variance was explained by age, IAI and C-reactive protein (CRP) (all positively associated); 10.9 % of the disability progression variance was predicted by IAI and CRP (both positively) and 25-hydroxyvitamin D (negatively), whereas 54.4 % of the severity index (MS-EDSS-MSSS) was explained by the regression on age, IAI, homocysteine, folate, and CRP (all positively), and adiponectin, body mass index, and 25-hydroxyvitamin D (all negatively), female sex, and the MTHFR 677 TT genotype. In patients and controls, 16.6 % of the variance in the homocysteine was explained by the MTHFR 677 TT genotype and age (both positively), folate (negatively) and male sex. CONCLUSION The MTHFR 677C>T variant has an indirect effect on the increase in disability in patients with MS, which also depends on factors such as age, sex, ad folate status.
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Affiliation(s)
- Claudia Mara Ribeiro
- Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil
| | - Sayonara Rangel Oliveira
- Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil; Department of Pathology, Clinical Analysis, and Toxicology, Health Sciences Center, State University of Londrina, Paraná, Brazil
| | - Tamires Flauzino
- Experimental Pathology Postgraduate Program, Biological Sciences Center, State University of Londrina, Londrina, Paraná, Brazil
| | - Daniela Frizon Alfieri
- Department of Pharmaceutical Sciences, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil
| | - Andrea Name Colado Simão
- Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil; Department of Pathology, Clinical Analysis, and Toxicology, Health Sciences Center, State University of Londrina, Paraná, Brazil
| | - Marcell Alysson Batisti Lozovoy
- Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil; Department of Pathology, Clinical Analysis, and Toxicology, Health Sciences Center, State University of Londrina, Paraná, Brazil
| | - Michael Maes
- Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, PR China; Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu 610072, PR China
| | - Edna Maria Vissoci Reiche
- Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil; Catholic Pontifical University, School of Medicine, Campus Londrina, Londrina, Paraná, Brazil.
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Chiu MH, Chang CH, Tantoh DM, Hsu TW, Hsiao CH, Zhong JH, Liaw YP. Susceptibility to hypertension based on MTHFR rs1801133 single nucleotide polymorphism and MTHFR promoter methylation. Front Cardiovasc Med 2023; 10:1159764. [PMID: 37849939 PMCID: PMC10577234 DOI: 10.3389/fcvm.2023.1159764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 09/11/2023] [Indexed: 10/19/2023] Open
Abstract
Background The aetio-pathologenesis of hypertension is multifactorial, encompassing genetic, epigenetic, and environmental factors. The combined effect of genetic and epigenetic changes on hypertension is not known. We evaluated the independent and interactive association of MTHFR rs1801133 single nucleotide polymorphism (SNP) and MTHFR promoter methylation with hypertension among Taiwanese adults. Methods We retrieved data including, MTHFR promoter methylation, MTHFR rs1801133 genotypes (CC, CT, and TT), basic demography, personal lifestyle habits, and disease history of 1,238 individuals from the Taiwan Biobank (TWB). Results The distributions of hypertension and MTHFR promoter methylation quartiles (β < 0.1338, 0.1338 ≤ β < 0.1385, 0.1385 ≤ β < 0.1423, and β ≥ 0.1423 corresponding to Conclusion Independently, rs1801133 TT was associated with a higher risk of hypertension, but methylation was not. Based on genotypes, lower methylation was dose-dependently associated with a higher risk of hypertension in individuals with the CC genotype. Our findings suggest that MTHFR rs1801133 and MTHFR promoter methylation could jointly influence hypertension susceptibility.
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Affiliation(s)
- Ming-Huang Chiu
- Department of Pulmonology and Respiratory Care, Cathay General Hospital, Taipei City, Taiwan
| | - Chia-Hsiu Chang
- Cardiovascular Center, Cathay General Hospital, Taipei City, Taiwan
| | - Disline Manli Tantoh
- Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, Taiwan
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
| | - Tsui-Wen Hsu
- Superintendent Office, Institute of Medicine, Cathay General Hospital, Taipei City, Taiwan
| | - Chih-Hsuan Hsiao
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
| | - Ji-Han Zhong
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
| | - Yung-Po Liaw
- Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, Taiwan
- Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung City, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung City, Taiwan
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Zhao L, Li T, Dang M, Li Y, Fan H, Hao Q, Song D, Lu J, Lu Z, Jian Y, Wang H, Wang X, Wu Y, Zhang G. Association of methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C>T) gene polymorphism with ischemic stroke risk in different populations: An updated meta-analysis. Front Genet 2023; 13:1021423. [PMID: 36685916 PMCID: PMC9845415 DOI: 10.3389/fgene.2022.1021423] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 11/29/2022] [Indexed: 01/05/2023] Open
Abstract
Background: Recently, increasing evidence has implicated methylenetetrahydrofolate reductase (MTHFR) gene mutation as a risk factor for ischemic stroke (IS) in the general population. However, studies have been inconclusive and lack evidence on specific populations. We aim to determine whether the rs1801133 (NC_000001.11 (MTHFR):g. 677C>T (p.Ala222Val) variant, we termed as MTHFR rs1801133 (677 C>T), is linked to an increased risk of IS in different age groups and ancestry groups. Methods: The literature relevant to our study was found by searching the PubMed, Cochrane Library, Web of Science, EMBASE, and CNKI databases. A random effect model analysis was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate any possible association. We conducted a subgroup analysis based on the age and ancestry groups of the included populations. Results: As of March 2022, 1,925 citations had been identified in electronic databases, of which 96 studies involving 34,814 subjects met our eligibility criteria. A strong link was found between IS and the MTHFR gene rs1801133 (677C>T) polymorphism in all genetic models [dominant genetic model (OR = 1.47; 95%CI = 1.33-1.61; p < 0.001), recessive genetic model (OR = 1.52; 95%CI = 1.36-1.71; p < 0.001), heterozygous model (OR = 1.36; 95%CI = 1.24-1.48; p < 0.001), homozygous model (OR = 1.82; 95%CI = 1.58-2.11; p < 0.001), and T allelic genetic model (OR = 1.37; 95%CI = 1.27-1.48; p < 0.001)]. Further subgroup analyses indicated that the MTHFR rs1801133 (677C>T) variant may increase the risk of IS in Asian, Hispanic, or Latin population, middle-aged, and elderly populations (p < 0.001). Conclusion: Our results implied that mutation of the T allele of MTHFR rs1801133 (677C>T) could be a risk factor for IS. A significant association was found among Asian, Hispanic, or Latin population, middle-aged, and elderly people.
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Affiliation(s)
- Lili Zhao
- Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Tao Li
- Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Meijuan Dang
- Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Ye Li
- Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Hong Fan
- Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Qian Hao
- Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Dingli Song
- Department of Thoracic Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jialiang Lu
- Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Ziwei Lu
- Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yating Jian
- Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Heying Wang
- Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xiaoya Wang
- Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yulun Wu
- Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Guilian Zhang
- Department of Neurology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China,*Correspondence: Guilian Zhang,
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Butnariu LI, Florea L, Badescu MC, Țarcă E, Costache II, Gorduza EV. Etiologic Puzzle of Coronary Artery Disease: How Important Is Genetic Component? LIFE (BASEL, SWITZERLAND) 2022; 12:life12060865. [PMID: 35743896 PMCID: PMC9225091 DOI: 10.3390/life12060865] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/05/2022] [Accepted: 06/08/2022] [Indexed: 12/11/2022]
Abstract
In the modern era, coronary artery disease (CAD) has become the most common form of heart disease and, due to the severity of its clinical manifestations and its acute complications, is a major cause of morbidity and mortality worldwide. The phenotypic variability of CAD is correlated with the complex etiology, multifactorial (caused by the interaction of genetic and environmental factors) but also monogenic. The purpose of this review is to present the genetic factors involved in the etiology of CAD and their relationship to the pathogenic mechanisms of the disease. Method: we analyzed data from the literature, starting with candidate gene-based association studies, then continuing with extensive association studies such as Genome-Wide Association Studies (GWAS) and Whole Exome Sequencing (WES). The results of these studies revealed that the number of genetic factors involved in CAD etiology is impressive. The identification of new genetic factors through GWASs offers new perspectives on understanding the complex pathophysiological mechanisms that determine CAD. In conclusion, deciphering the genetic architecture of CAD by extended genomic analysis (GWAS/WES) will establish new therapeutic targets and lead to the development of new treatments. The identification of individuals at high risk for CAD using polygenic risk scores (PRS) will allow early prophylactic measures and personalized therapy to improve their prognosis.
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Affiliation(s)
- Lăcrămioara Ionela Butnariu
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (L.I.B.); (E.V.G.)
| | - Laura Florea
- Department of Nefrology—Internal Medicine, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania;
| | - Minerva Codruta Badescu
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iași, Romania
- III Internal Medicine Clinic, “St. Spiridon” County Emergency Clinical Hospital, 1 Independence Boulevard, 700111 Iași, Romania
- Correspondence: (M.C.B.); (E.Ț.)
| | - Elena Țarcă
- Department of Surgery II—Pediatric Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Correspondence: (M.C.B.); (E.Ț.)
| | - Irina-Iuliana Costache
- Department of Internal Medicine (Cardiology), “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iași, Romania;
| | - Eusebiu Vlad Gorduza
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (L.I.B.); (E.V.G.)
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Phillips-Chavez C, Coward J, Watson M, Schloss J. A Retrospective Cross-Sectional Cohort Trial Assessing the Prevalence of MTHFR Polymorphisms and the Influence of Diet on Platinum Resistance in Ovarian Cancer Patients. Cancers (Basel) 2021; 13:5215. [PMID: 34680361 PMCID: PMC8533864 DOI: 10.3390/cancers13205215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/12/2021] [Accepted: 10/14/2021] [Indexed: 11/29/2022] Open
Abstract
Ovarian cancer has the lowest survival rate in gynaecologic malignancies with a 5-year survival rate of 43%. Platinum resistance is one of the main drivers of ovarian cancer mortality, of which aberrant methylation has been cited as a significant contributor. Understanding the essential role of the methylenetetrahydrofolate reductase enzyme (MTHFR) on DNA synthesis and repair, and how nutrient status can vastly affect its performance, led to the investigation of MTHFR status and dietary influence on platinum response in epithelial ovarian cancer (EOC) patients. Twenty-five adult female patients who completed first-line platinum-based chemotherapy for primary ovarian cancer were selected from Icon Cancer Centres in Australia. Participants were grouped based on platinum response. A full medical and family history, food frequency questionnaire and single blood test were completed, testing for MTHFR polymorphisms, serum folate, serum and active B12 and homocysteine levels. Nineteen of twenty-five participants had an MTHFR polymorphism. Of those, 20% were compound heterozygous, 12% were heterozygous C677T (CT), 4% homozygous C677T, 12% homozygous A1298C and 28% were heterozygous A1298C (AC). Statistically significant associations were found between dietary zinc (p = 0.0086; 0.0030; 0.0189) and B12 intakes in CT genotypes (p = 0.0157; 0.0030; 0.0068) indicating that zinc or vitamin B12 intakes below RDI were associated with this genotype. There were strong associations of vitamin B6 intakes in AC genotypes (p = 0.0597; 0.0547; 0.0610), and dietary folate in compound heterozygotes with sensitive and partially sensitive disease (p = 0.0627; 0.0510). There were also significant associations between serum folate (p = 0.0478) and dietary B12 (p = 0.0350) intakes above RDI and platinum sensitivity in wild-types as well as strong associations with homocysteine levels (p = 0.0886) and zinc intake (p = 0.0514). Associations with dietary B12 (p = 0.0514) and zinc intakes (p = 0.0731) were also strong in resistant wild types. Results indicate that dietary zinc, B12 and B6 intakes may be associated with platinum sensitivity dependent on MTHFR genotype. These results require further research to clarify the dosages necessary to elicit a response; however, they provide a novel foundation for acknowledging the role of diet on treatment response in EOC.
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Affiliation(s)
- Caitlin Phillips-Chavez
- Icon Cancer Centre, Queensland, Australia;
- Endeavour College of Natural Health, Brisbane, QLD 4006, Australia;
| | - Jermaine Coward
- Icon Cancer Centre, Queensland, Australia;
- School of Medicine, University of Queensland, Brisbane, QLD 4006, Australia
| | - Michael Watson
- Endeavour College of Natural Health, Brisbane, QLD 4006, Australia;
- Institute of Health & Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4006, Australia
| | - Janet Schloss
- NCNM, Southern Cross University, Lismore, NSW 2480, Australia;
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Yang P, Wang L, Tang X, Liang Y. The methylenetetrahydrofolate reductase 1298 A>C polymorphism is associated with an increased risk of inflammatory bowel disease: evidence from a meta-analysis. Expert Rev Clin Immunol 2021; 17:1221-1229. [PMID: 34528870 DOI: 10.1080/1744666x.2021.1982384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE The association between genetic variants in methylenetetrahydrofolate reductase (MTHFR) and risk for inflammatory bowel disease (IBD) has been widely studied. However, the results are equivocal. In this meta-analysis, we aimed to determine the association between MTHFR polymorphisms and susceptibility to IBD. METHODS We retrieved studies from the PubMed, Web of Science, Ovid, and China National Knowledge Infrastructure databases. Data were analyzed using STATA software; odds ratios (OR) and confidence intervals (CI) were calculated using fixed or random effects models. RESULTS A marginally significant association of the MTHFR 677 C > T polymorphism and patients' IBD risk was observed in the overall analysis (OR = 1.11, 95% CI, 1.01-1.23), but not in the analysis of high-quality studies. However, for the MTHFR 1298 A > C polymorphism, a significant association was found between the MTHFR 1298 AC/CC genotypes and IBD risk in the overall analysis (OR = 1.26, 95% CI, 1.10-1.44), in the high-quality studies (OR = 1.20, 95% CI, 1.02-1.41), and in patients with ulcerative colitis (OR = 1.28, 95% CI, 1.10-1.48). CONCLUSIONS Evidence from this meta-analysis indicates that the MTHFR 1298 A > C polymorphism may be responsible for susceptibility to IBD and ulcerative colitis.
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Affiliation(s)
- Pingliang Yang
- Department of Anesthesiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, P.R. China
| | - Li Wang
- Department of Anesthesiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, P.R. China
| | - Xingming Tang
- Department of Anesthesiology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, P.R. China
| | - Yundan Liang
- Department of Pathology and Pathophysiology, Chengdu Medical College, Chengdu, P.R. China
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Cassinadane AV, Ramasamy R, Lenin M, Velu K, Hussain SA. Association of MTHFR (rs 1801133) gene polymorphism with biochemical markers of B12 deficiency in type 2 diabetes mellitus patients on metformin therapy. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Qian XL, Cao H, Zhang J, Gu ZH, Tang WQ, Shen L, Hu JL, Yao ZF, Zhang L, Tang MN, Lv XC, Zhou J, Jin XJ, Hong B, Cui ZQ, Ge JB. The prevalence, relative risk factors and MTHFR C677T genotype of H type hypertension of the elderly hypertensives in Shanghai, China: a cross-section study : Prevalence of H type hypertension. BMC Cardiovasc Disord 2021; 21:376. [PMID: 34348647 PMCID: PMC8336333 DOI: 10.1186/s12872-021-02151-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 06/25/2021] [Indexed: 12/27/2022] Open
Abstract
Background H type hypertension is defined as homocysteine (Hcy) ≥ 10 μmol/L in combination with primary hypertension. Studies demonstrated that the existence of hyperhomocysteine (HHcy) in hypertensive exacerbates the poor outcome of cardiocerebral incidents. This study was to investigate the current epidemic situation of H type hypertension and determine the risk factors in order to find intervention targets for H type hypertensives. Methods We conducted a cross-sectional study using cluster sampling design in Shanghai, China from July 2019 and April 2020. 23,652 patients with primary hypertension were enrolled in this study. Their medical information was recorded, and the level of Hcy concentrations and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms were detected. Results In total, 22,731 of 23,652 patients were recorded. The mean age was 68.9 ± 8.6 y and 43% were men. 80.0% of the enrolled patients had H type hypertension. The frequency of allele T was 40.9%, and the proportions of the CC, CT, and TT genotypes were 36.1%, 46.0%, and 17.9%, respectively. Compared with the TT genotype, the plasma Hcy concentration levels were lower in patients with the CC/CT genotype (18.96 ± 13.48 μmol/L vs. 13.62 ± 5.20/14.28 ± 5.36, F = 75.04, p < 0.01). The risk for H type hypertension was higher in elderly people. Men had ~ 5.55-fold odds of H type hypertension compared with women. Patients with CT genotype and TT genotype had ~ 1.36- and ~ 2.76-fold odds of H type hypertension compared with those with CC genotype, respectively. Smoking and diabetes were not significantly associated with H type hypertension. Conclusions The prevalence of H type hypertension in patients with primary hypertension was 80.0%, which was higher than the 75% found in prior report in China. Age, gender, and MTHFR C677T polymorphisms rather than smoking and diabetes were independently associated with H type hypertension.
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Affiliation(s)
- Xiao-Lin Qian
- Department of Cardiology, QingPu Branch of Zhongshan Hospital Affiliated to Fudan University, QingPu District Central Hospital Shanghai, Shanghai, China
| | - Hong Cao
- Department of Cardiology, QingPu District Jinze Community Health Center, Shanghai, China
| | - Jun Zhang
- Department of Cardiology, QingPu District Xujing Community Health Center, Shanghai, China
| | - Zhi-Hui Gu
- Department of Cardiology, QingPu District Zhujiajiao Community Health Center, Shanghai, China
| | - Wei-Qin Tang
- Department of Cardiology, QingPu District Xianghuaqiao Community Health Center, Shanghai, China
| | - Lei Shen
- Department of Cardiology, QingPu District Yingpu Community Health Center, Shanghai, China
| | - Jia-Lu Hu
- Department of Cardiology, Shanghai Institute of Cardiovascular Disease and Zhongshan Hospital Fudan University, Shanghai, China
| | - Zhi-Feng Yao
- Department of Cardiology, Shanghai Institute of Cardiovascular Disease and Zhongshan Hospital Fudan University, Shanghai, China
| | - Lei Zhang
- Department of Cardiology, Shanghai Institute of Cardiovascular Disease and Zhongshan Hospital Fudan University, Shanghai, China
| | - Min-Na Tang
- Department of Cardiology, Shanghai Institute of Cardiovascular Disease and Zhongshan Hospital Fudan University, Shanghai, China
| | - Xu-Cheng Lv
- Department of Cardiology, Shanghai Institute of Cardiovascular Disease and Zhongshan Hospital Fudan University, Shanghai, China
| | - Jun Zhou
- Department of Cardiology, Shanghai Institute of Cardiovascular Disease and Zhongshan Hospital Fudan University, Shanghai, China
| | - Xue-Juan Jin
- Department of Cardiology, Shanghai Institute of Cardiovascular Disease and Zhongshan Hospital Fudan University, Shanghai, China
| | - Bin Hong
- Department of Cardiology, Shanghai Zhujiajiao People's Hospital, Shanghai, China.
| | - Zhao-Qiang Cui
- Department of Cardiology, Shanghai Institute of Cardiovascular Disease and Zhongshan Hospital Fudan University, Shanghai, China.
| | - Jun-Bo Ge
- Department of Cardiology, Shanghai Institute of Cardiovascular Disease and Zhongshan Hospital Fudan University, Shanghai, China.
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Liu M, Yu J, Su Z, Sun Y, Liu Y, Xie Q, Li Z, Wang L, Zhang J, Jin L, Ren A. Associations between prenatal exposure to cadmium and lead with neural tube defect risks are modified by single-nucleotide polymorphisms of fetal MTHFR and SOD2: a case-control study. Environ Health 2021; 20:66. [PMID: 34090432 PMCID: PMC8180011 DOI: 10.1186/s12940-021-00752-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 05/24/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND Prenatal exposure to heavy metals is implicated in the etiology of birth defects. We investigated whether concentrations of cadmium (Cd) and lead (Pb) in umbilical cord tissue are associated with risk for neural tube defects (NTDs) and whether selected genetic variants of the fetus modify their associations. METHODS This study included 166 cases of NTD fetuses/newborns and 166 newborns without congenital malformations. Umbilical cord tissue was collected at birth or elective pregnancy termination. Cd and Pb concentrations were assessed by inductively coupled plasma-mass spectrometry, and 20 single-nucleotide polymorphisms (SNPs) in 9 genes were genotyped. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the risk for NTDs in association with metal concentrations or genotype using logistic regression. Multiplicative-scale interactions between the metals and genotypes on NTD risk were assessed with logistic regression, and additive-scale interactions were estimated with a non-linear mixed effects model. RESULTS Higher concentrations of Cd were observed in the NTD group than in the control group, but no difference was found for Pb. Concentrations of Cd above the median level showed a risk effect, while the association between Pb and NTD risk was not significant in univariate analyses. The association of Cd was attenuated after adjusting for periconceptional folic acid supplementation. Fetuses with the AG and GG genotypes of rs4880 in SOD2 (superoxide dismutase 2) tended to have a lower risk, but fetuses with the CT and TT genotypes of rs1801133 in MTHFR (5,10-methylenetetrahydrofolatereductase) have a higher risk for NTDs when compared to their respective wild-type. rs4880 and Cd exhibited a multiplicative-scale interaction on NTD risk: the association between higher Cd and the risk for NTDs was increased by over fourfold in fetuses carrying the G allele [OR 4.43 (1.30-15.07)] compared to fetuses with the wild-type genotype. rs1801133 and Cd exposure showed an additive interaction, with a significant relative excess risk of interaction [RERI 0.64 (0.02-1.25)]. CONCLUSIONS Prenatal exposure to Cd may be a risk factor for NTDs, and the risk effect may be enhanced in fetuses who carry the G allele of rs4880 in SOD2 and T allele of rs1801133 in MTHFR.
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Affiliation(s)
- Mengyuan Liu
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Jinhui Yu
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Zaiming Su
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Ying Sun
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Yaqiong Liu
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Qing Xie
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Zhiwen Li
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Linlin Wang
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Jie Zhang
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Lei Jin
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
| | - Aiguo Ren
- Institute of Reproductive and Child Health/Key Laboratory of Reproductive Health, National Health Commission of the People’s Republic of China, Peking University, Beijing, China
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
- Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China
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10
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Wu X, Lin J, Xue N, Teng J, Wang Y, Li Y, Xu X, Shen Z, Ding X, Fang Y. Relationship Between Gene Polymorphism of Methylenetetrahydrofolate Reductase C677T and Left Ventricular Hypertrophy in Chinese Patients with Chronic Kidney Disease. Lab Med 2021; 52:519-527. [PMID: 33693817 DOI: 10.1093/labmed/lmab004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE This study aimed to investigate the relationship between the gene polymorphism of methylenetetrahydrofolate reductase (MTHFR) C677T and left ventricular hypertrophy (LVH) in patients with chronic kidney disease (CKD). METHODS A total of 763 Chinese patients with CKD undergoing genetic testing were included in the study. The association between the gene polymorphism of MTHFR C677T and echocardiographic parameters was analyzed through univariate and multivariate analyses. RESULTS We found a remarkably positive association between MTHFR C677T gene polymorphism and LVH indexes, including interventricular septal thickness (F = 3.8; P = .022), left ventricular posterior wall thickness (F = 3.0; P = .052), left ventricular mass (F = 3.9; P = .022), and left ventricular mass index (F = 2.6; P = .075). After adjusting for the potential confounders linking the polymorphism,we found that the positive association between the polymorphism and LVH indexes still existed in patients with CKD in some multiple linear regression models (P <.05). CONCLUSION MTHFR C677T gene polymorphism may be a genetic susceptibility marker for the development of LVH in patients with CKD.
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Affiliation(s)
- Xie Wu
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Kidney and Blood Purification, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Lin
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Kidney and Blood Purification, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical Center of Kidney Disease, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Kidney and Dialysis, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ning Xue
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical Center of Kidney Disease, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Kidney and Dialysis, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jie Teng
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Kidney and Blood Purification, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical Center of Kidney Disease, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Kidney and Dialysis, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yaqiong Wang
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical Center of Kidney Disease, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Kidney and Dialysis, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yang Li
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Kidney and Blood Purification, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xunhui Xu
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Kidney and Blood Purification, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ziyan Shen
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical Center of Kidney Disease, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Kidney and Dialysis, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaoqiang Ding
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Kidney and Blood Purification, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical Center of Kidney Disease, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Kidney and Dialysis, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi Fang
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Kidney and Blood Purification, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical Center of Kidney Disease, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Kidney and Dialysis, Zhongshan Hospital, Fudan University, Shanghai, China
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11
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Muzurović E, Kraljević I, Solak M, Dragnić S, Mikhailidis DP. Homocysteine and diabetes: Role in macrovascular and microvascular complications. J Diabetes Complications 2021; 35:107834. [PMID: 33419630 DOI: 10.1016/j.jdiacomp.2020.107834] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/23/2020] [Accepted: 12/17/2020] [Indexed: 01/12/2023]
Abstract
Diabetes mellitus (DM) can lead to the development of macro- and microvascular complications. Homocysteine (Hcy) may play a role in the development of cardiovascular (CV) diseases (CVDs). The role of Hcy in the development of the vascular complications associated with DM is not clearly defined. Despite a strong initial assumption regarding the importance of Hcy in DM and its complications, over time "enthusiasm has waned" because several studies showed unconvincing and occasionally contradictory results. A universal conclusion is not easy to draw given the diversity of studies (e.g. number of patients, design, folic acid and vitamin B status, ethnic differences, genetic background). For some complications, most results encourages further investigation. Impaired renal function is a major independent determinant of high total Hcy (tHcy) levels. However, the role of hyperhomocysteinaemia (HHcy) in the development of diabetic kidney disease (DKD) has yet to be determined. Hcy-lowering therapies can significantly decrease Hcy levels but their effects on CVD risk reduction are conflicting. Further studies are needed to determine the influence of Hcy-lowering therapy on CVD risk reduction, especially in patients with DM.
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Affiliation(s)
- Emir Muzurović
- Department of Internal Medicine, Endocrinology Section, Clinical Centre of Montenegro, Faculty of Medicine, University of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro.
| | - Ivana Kraljević
- Department of Endocrinology, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Mirsala Solak
- Department of Endocrinology, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Siniša Dragnić
- Department of Cardiology, Clinical Centre of Montenegro, Faculty of Medicine, University of Montenegro, Ljubljanska bb, 81000 Podgorica, Montenegro
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), Pond Street, London NW3 2QG, UK
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12
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Folate metabolism: Impact of involved genetic variants on homocycteine and folate levels in type 2 diabetic patients with coronary artery disease. Meta Gene 2020. [DOI: 10.1016/j.mgene.2020.100817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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13
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Nedelcu C, Ionescu M, Pantea-Stoian A, Niţă D, Petcu L, Mazilu L, Suceveanu AI, Tuţă LA, Parepa IR. Correlation between plasma homocysteine and first myocardial infarction in young patients: Case-control study in Constanta County, Romania. Exp Ther Med 2020; 21:101. [PMID: 33363612 DOI: 10.3892/etm.2020.9533] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 10/30/2020] [Indexed: 11/06/2022] Open
Abstract
An elevated level of total plasma homocysteine has been associated with a higher risk of atherosclerosis and coronary heart disease. The aim of our research was to study the relation between homocysteine and myocardial infarction (MI) in young patients. We conducted a case-control study in Constanţa County, Romania including 61 patients, divided in two groups. The first group, the MI group, consisted of 28 patients, male (67.9%) and female (32.1%) aged less than 45 years who were consecutively admitted to the Intensive Coronary Care Unit of the Emergency County Hospital of Constanţa from September 1, 2017 to August 31, 2018 (12 months), with an established diagnosis of first acute MI. The second group, the control group, included 33 patients, male (75.8%) and female (24.2%) aged less than 45 years, with cardiovascular risk factors and/or stable angina pectoris that were consecutively addressed for ambulatory cardiac evaluation at the Outpatient Clinic of Emergency County Hospital of Constanţa during the same period. Fasting plasma homocysteine was determined in both groups, within 24 h after MI onset, respectively after first cardiac exam in the controls. High homocysteine was statistically confirmed to be a risk factor in the study group, especially in association with smoking, chronic kidney disease (CKD), and to a lesser extent with diabetes mellitus (DM) and hypertension. Data analysis was performed using IBM SPSS Statistics 23. The procedures used included descriptive statistics, parametric statistical tests (Independent sample t-test), non-parametric statistical tests [Chi-square test of the association, with the evaluation of odds ratio (OR)]; the significance level used in the analysis (P-value) was 0.05. After adjusting for variables, our study results pointed out a strong association between plasma homocysteine and first acute MI among young patients, emphasising plasma homocysteine as a possible risk factor for myocardial infarction.
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Affiliation(s)
- Cristina Nedelcu
- Cardiology Department, Constanta County Army Hospital, 900527 Constanţa, Romania
| | - Mihaela Ionescu
- Department of Clinical Medical Sciences, Faculty of General Medicine, 'Ovidius' University of Constanţa, 900527 Constanţa, Romania
| | - Anca Pantea-Stoian
- Department of Metabolic Diseases of the Clinical Emergency Hospital, 'Carol Davila' University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania
| | - Daniel Niţă
- Department of Interventional Cardiology, Army's Center for Cardiovascular Diseases, 010825 Bucharest, Romania
| | - Lucian Petcu
- Department of Biophysics, Faculty of General Medicine, 'Ovidius' University of Constanţa, 900527 Constanta, Romania
| | - Laura Mazilu
- Department of Clinical Medical Sciences, Faculty of General Medicine, 'Ovidius' University of Constanţa, 900527 Constanţa, Romania
| | - Andra-Iulia Suceveanu
- Department of Clinical Medical Sciences, Faculty of General Medicine, 'Ovidius' University of Constanţa, 900527 Constanţa, Romania
| | - Liliana-Ana Tuţă
- Department of Clinical Medical Sciences, Faculty of General Medicine, 'Ovidius' University of Constanţa, 900527 Constanţa, Romania
| | - Irinel-Raluca Parepa
- Department of Clinical Medical Sciences, Faculty of General Medicine, 'Ovidius' University of Constanţa, 900527 Constanţa, Romania
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14
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Zheng XZ, Bian XL, Sun ZH, Wang HD. Interaction Between Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphisms and Environment with Susceptibility to Ischemic Stroke in Chinese Population. Ann Indian Acad Neurol 2020; 23:491-495. [PMID: 33223666 PMCID: PMC7657291 DOI: 10.4103/aian.aian_192_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 05/04/2019] [Accepted: 05/20/2019] [Indexed: 12/11/2022] Open
Abstract
Aims: To investigate the association of several single-nucleotide polymorphisms (SNPs) within methylenetetrahydrofolate reductase (MTHFR) gene, and additional gene–environment interaction with ischemic stroke (IS) risk. Methods: Testing for Hardy–Weinberg equilibrium in controls was conducted using SNPstats (online software: http://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among four SNPs within MTHFR gene and smoking or alcohol drinking. Results: The frequency of the rs4846049-A allele was 28.6% in IS patients and 19.1% in normal controls, in addition, the frequency of the rs3737967-T allele was 27.9% in IS patients and 20.3% in normal controls, which was also indicating a statistically significant difference. The rs4846049-A and rs3737967-T were associated with an increased risk of IS risk; adjusted odds ratios (ORs) (95% confidence interval [CI]) were 1.76 (1.28–2.13) and 1.51 (1.13–1.97), respectively. GMDR model found significant gene–alcohol drinking interaction combination, but no significant gene–tobacco smoking interaction combinations. In order to obtain the odds ratios and 95% CI for the joint effects of gene–alcohol drinking on IS, we conducted stratified analysis for interaction effect using logistic regression. We found that alcohol drinkers with rs4846049-CA/AA genotype also have the highest IS risk, compared with never drinkers with rs4846049-CC genotype, OR (95% CI) = 3.12 (1.83–4.45), after adjustment for age, smoke, and smoking status. Conclusions: The rs4846049-A and rs3737967-T, gene–environment interaction between rs1764391 and rs918592, gene–environment interaction between rs4846049 and alcohol drinking were all associated with increased IS risk.
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Affiliation(s)
- Xing-Zhen Zheng
- Department of Emergency, Tianjin Nankai Hospital, Tianjin, China
| | - Xiao-Lin Bian
- Department of Emergency, Tianjin Nankai Hospital, Tianjin, China
| | - Zhe-Hong Sun
- Department of Emergency, Tianjin Nankai Hospital, Tianjin, China
| | - Hai-Dong Wang
- Department of Emergency, Tianjin Nankai Hospital, Tianjin, China
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15
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Association of single nucleotide polymorphisms of MTHFR, TCN2, RNF213 with susceptibility to hypertension and blood pressure. Biosci Rep 2020; 39:221446. [PMID: 31815282 PMCID: PMC6923352 DOI: 10.1042/bsr20191454] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 11/28/2019] [Accepted: 12/07/2019] [Indexed: 12/19/2022] Open
Abstract
Methylenetetrahydrofolate reductase gene (MTHFR), transcobalaminII (TCN2) and ring finger protein 213 (RNF213) are related to homocysteine (Hcy) level and are of great significance for hypertension. We aimed to evaluate the associations of MTHFR (rs1801133, rs1801131, rs9651118), TCN2 (rs117353193) and RNF213 (rs9916351) with hypertension and blood pressure (BP). A total of 953 patients with hypertension and 1103 controls were enrolled. Genotyping was performed by Taqman. Logistic regression analysis indicated that A allele of TCN2 rs117353193 under the dominant model had a significantly protective effect (P=0.045) after adjustment, which showed that AA+GA genotype has a lower risk than GG. Additionally, the average diastolic BP (DBP) (P=0.044) and mean arterial pressure (MAP) (P=0.035) levels were significantly different between genotypes of RNF213 rs9916351. Further pairwise comparison showed that the average systolic BP (SBP) level of the TT genotype carriers were significantly higher than in CC (P=0.024), and the average DBP and MAP levels of the TT genotype carriers were higher than in CT (P=0.044, P=0.012, respectively) and CC (P=0.048, P=0.010, respectively). In the recessive model, the average SBP (P=0.043), DBP (P=0.018) and MAP (P=0.017) levels with the TT genotype carriers were significantly higher than in CT+CC. Multiple linear regression analysis suggested that RNF213 rs9916351 in the recessive model had significant effects on SBP (P=0.025), DBP (P=0.017) and MAP (P=0.010) as a risk factor. However, no associations were observed between MTHFR and hypertension. TCN2 rs117353193 might serve as a protective factor in hypertension, and RNF213 rs9916351 might be a risk factor that is linked to increase BP level in Northeast Chinese population.
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16
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Calderón-Larrañaga A, Saadeh M, Hooshmand B, Refsum H, Smith AD, Marengoni A, Vetrano DL. Association of Homocysteine, Methionine, and MTHFR 677C>T Polymorphism With Rate of Cardiovascular Multimorbidity Development in Older Adults in Sweden. JAMA Netw Open 2020; 3:e205316. [PMID: 32432712 PMCID: PMC7240355 DOI: 10.1001/jamanetworkopen.2020.5316] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
IMPORTANCE Strong evidence links high total serum homocysteine (tHcy) and low methionine (Met) levels with higher risk of ischemic disease, but other cardiovascular (CV) diseases may also be associated with their pleiotropic effects. OBJECTIVES To investigate the association of serum concentrations of tHcy and Met with the rate of CV multimorbidity development in older adults and to explore the role of methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism in this association. DESIGN, SETTING, AND PARTICIPANTS The Swedish National Study on Aging and Care in Kungsholmen is a cohort study of randomly selected individuals aged 60 years or older. The present study included data on 1969 individuals with complete information and without CV diseases at baseline, collected from the baseline examination (2001-2004) to the fourth follow-up (2013-2016). Data analysis was conducted from January to May 2019. EXPOSURES Concentrations of tHcy and Met were measured from nonfasting venous blood samples. The Met:tHcy ratio was considered a possible indicator of methylation activity. MTHFR status was dichotomized as any T carriers vs noncarriers. MAIN OUTCOME AND MEASURES The number of CV diseases at each wave was ascertained based on medical interviews and records, laboratory test results, and drug data. Linear mixed models were used to study the association of baseline tHcy and Met levels and the rate of CV multimorbidity development, adjusting for sociodemographic characteristics, CV risk factors, chronic disease burden, and drug use. RESULTS Of 1969 participants, most were women (1261 [64.0%]), with a mean (SD) age of 70.9 (9.8) years; 1703 participants (86.6%) had at least a high school level of education. Baseline measurements of serum tHcy, Met, and the Met:tHcy ratio were associated with the rate of CV disease accumulation (tHcy: β = 0.023 per year; 95% CI, 0.015 to 0.030; P < .001; Met: β = -0.007 per year; 95% CI, -0.013 to -0.001; P = .02; Met:tHcy ratio: β = -0.017 per year; 95% CI, -0.023 to -0.011; P < .001). The association between low Met concentrations and the rate of CV multimorbidity development was restricted to the group with CT/TT alleles of MTHFR (β = 0.023 per year; 95% CI, 0.006 to 0.041; P = .009). Results remained largely significant when individual CV diseases were removed from the total count 1 at a time (eg, ischemic heart disease, tHcy: β = 0.023 per year; 95% CI, 0.013 to 0.027; P < .001; Met: β = -0.006 per year; 95% CI, -0.011 to -0.0003; P = .04; Met:tHcy ratio: β = -0.015 per year; 95% CI, -0.020 to -0.009; P < .001). CONCLUSIONS AND RELEVANCE In this study, high tHcy and low Met levels were associated with faster CV multimorbidity development in older age. The interactive association of Met concentrations and MTHFR polymorphism, together with the association found for the Met:tHcy ratio, point toward the relevance of impaired methylation in the pathogenesis of CV aging.
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Affiliation(s)
- Amaia Calderón-Larrañaga
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden
| | - Marguerita Saadeh
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden
| | - Babak Hooshmand
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden
- Department of Neurology, Ulm University Hospital, Ulm, Germany
| | - Helga Refsum
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
- Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - A. David Smith
- Department of Pharmacology, University of Oxford, Oxford, United Kingdom
| | - Alessandra Marengoni
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Davide L. Vetrano
- Aging Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden
- Department of Geriatrics, Fondazione Policlinico “A. Gemelli” IRCCS and Catholic University of Rome, Rome, Italy
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17
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Hou J, Zhong Z, Deng Q, Lin L, Zeng X. The role of MTHFR C677T and ALDH2 Glu504Lys polymorphism in acute coronary syndrome in a Hakka population in southern China. BMC Cardiovasc Disord 2020; 20:127. [PMID: 32160861 PMCID: PMC7066809 DOI: 10.1186/s12872-020-01410-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 03/02/2020] [Indexed: 01/12/2023] Open
Abstract
Background Acute coronary syndrome (ACS) is the most serious type of coronary heart disease and is a global medical burden. The pathogenesis of ACS is very complex and still poorly understood. Epidemiologic studies have revealed that the manifestation of ACS are the results of the interactions between multiple environmental and genetic factors. The present study aimed to investigate the role of polymorphisms of MTHFR C677T and ALDH2 Glu504Lys as risk factors for ACS in a Hakka population in southern China. Methods Between September 1, 2015 and October 31, 2017, a total of 1957 individuals, including 860 ACS patients and 1097 controls were recruited. Blood samples were collected and genotypes were determined by DNA microarray chip method and direct sequencing method. Results For the MTHFR C677T polymorphism, frequencies of CC, CT, and TT genotypes were 53.60% versus 55.33, 39.53% versus 38.65 and 6.86% versus 6.02% in patients with ACS versus controls, respectively(p > 0.05). The differences in genotype frequencies between the ACS patients and controls in the three genetic model were not statistically significant. For the ALDH2 Glu504Lys polymorphism, the frequencies of ALDH2*1*1, ALDH2*1*2, and ALDH2*2*2 genotypes were 48.72, 42.67 and 8.6% in the ACS patients, respectively, while these were 53.33, 39.11 and 7.57% in the controls, respectively, showing no significant difference in the distribution of the ALDH2 genotype between the groups. Using the wild genotype ALDH2*1*1 as reference, relative risk analysis revealed a slightly increased risk for ACS in individuals with the ALDH2*1*2 plus ALDH2*2*2 genotypes (odds ratio (OR) = 1.203, 95% confidence interval (CI) = 1.006–1.438, p = 0.043). In a multivariate logistic regression model, even after adjusting for potential covariates, the association between ALDH2 *2 allele and ACS remained significant (OR = 1.242, 95% CI = 1.045–1.561, p = 0.038). Conclusions We present findings regarding the possible clinical impact of the ALDH2*2 variant on ACS patients in a Hakka population in southern China and our findings might help to stratify the high-risk ACS patients and implement appropriate strategies for this genetic subpopulation to ultimately guide the precision preventive procedures in the future.
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Affiliation(s)
- Jingyuan Hou
- Clinical Core Laboratory, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University, No. 63 Huangtang Road, Meijiang District, Meizhou, 514031, People's Republic of China. .,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, 514031, People's Republic of China. .,Guangdong Provincial Engineering and Technological Research Center for Molecular Diagnostics of Cardiovascular Diseases, Meizhou, 514031, People's Republic of China.
| | - Zhixiong Zhong
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, 514031, People's Republic of China.,Guangdong Provincial Engineering and Technological Research Center for Molecular Diagnostics of Cardiovascular Diseases, Meizhou, 514031, People's Republic of China.,Center for Cardiovascular Diseases, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, 514031, People's Republic of China
| | - Qiaoting Deng
- Clinical Core Laboratory, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University, No. 63 Huangtang Road, Meijiang District, Meizhou, 514031, People's Republic of China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, 514031, People's Republic of China.,Guangdong Provincial Engineering and Technological Research Center for Molecular Diagnostics of Cardiovascular Diseases, Meizhou, 514031, People's Republic of China
| | - Lifang Lin
- Clinical Core Laboratory, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University, No. 63 Huangtang Road, Meijiang District, Meizhou, 514031, People's Republic of China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, 514031, People's Republic of China.,Guangdong Provincial Engineering and Technological Research Center for Molecular Diagnostics of Cardiovascular Diseases, Meizhou, 514031, People's Republic of China
| | - Xing Zeng
- Clinical Core Laboratory, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-sen University, No. 63 Huangtang Road, Meijiang District, Meizhou, 514031, People's Republic of China.,Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, 514031, People's Republic of China.,Guangdong Provincial Engineering and Technological Research Center for Molecular Diagnostics of Cardiovascular Diseases, Meizhou, 514031, People's Republic of China
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Mei X, Qi D, Zhang T, Zhao Y, Jin L, Hou J, Wang J, Lin Y, Xue Y, Zhu P, Liu Z, Huang L, Nie J, Si W, Ma J, Ye J, Finnell RH, Saiyin H, Wang H, Zhao J, Zhao S, Xu W. Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects. EMBO Mol Med 2020; 12:e9469. [PMID: 32003121 PMCID: PMC7059139 DOI: 10.15252/emmm.201809469] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 12/16/2019] [Accepted: 12/19/2019] [Indexed: 02/05/2023] Open
Abstract
Hyperhomocysteinemia is a common metabolic disorder that imposes major adverse health consequences. Reducing homocysteine levels, however, is not always effective against hyperhomocysteinemia-associated pathologies. Herein, we report the potential roles of methionyl-tRNA synthetase (MARS)-generated homocysteine signals in neural tube defects (NTDs) and congenital heart defects (CHDs). Increased copy numbers of MARS and/or MARS2 were detected in NTD and CHD patients. MARSs sense homocysteine and transmit its signal by inducing protein lysine (N)-homocysteinylation. Here, we identified hundreds of novel N-homocysteinylated proteins. N-homocysteinylation of superoxide dismutases (SOD1/2) provided new mechanistic insights for homocysteine-induced oxidative stress, apoptosis and Wnt signalling deregulation. Elevated MARS expression in developing and proliferating cells sensitizes them to the effects of homocysteine. Targeting MARSs using the homocysteine analogue acetyl homocysteine thioether (AHT) reversed MARS efficacy. AHT lowered NTD and CHD onsets in retinoic acid-induced and hyperhomocysteinemia-induced animal models without affecting homocysteine levels. We provide genetic and biochemical evidence to show that MARSs are previously overlooked genetic determinants and key pathological factors of hyperhomocysteinemia, and suggest that MARS inhibition represents an important medicinal approach for controlling hyperhomocysteinemia-associated diseases.
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Urquhart BL, House AA. Assessing Plasma Total Homocysteine in Patients with End-Stage Renal Disease. Perit Dial Int 2020. [DOI: 10.1177/089686080702700502] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Elevated plasma total homocysteine (tHcy) is a risk factor for cardiovascular disease; however, in light of several recent randomized trials, the issue of causality has been cast into doubt. Patients with end-stage renal disease are particularly interesting as they consistently have elevated tHcy and their leading causes of morbidity and mortality are related to cardiovascular disease. In the present article, we review the early evidence for the homocysteine theory of atherosclerosis, homocysteine metabolism, mechanisms of toxicity, and pertinent available clinical investigations. Where appropriate, the sparse evidence of homocysteine in peritoneal dialysis is reviewed. We conclude by addressing the difficulties associated with lowering plasma tHcy in patients with end-stage renal disease and suggest some novel methods for lowering tHcy in this resistant population. Finally, to address the issue of causality, we recommend that clinicians and scientists await the results of the FAVORIT trial before abandoning homocysteine as a modifiable risk factor for cardiovascular disease, as this study has recruited patients from a population with consistently elevated plasma tHcy who are known to respond to vitamin therapy.
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Affiliation(s)
- Bradley L. Urquhart
- Departments of Medicine The University of Western Ontario, London, Ontario, Canada
- Physiology/Pharmacology, The University of Western Ontario, London, Ontario, Canada
| | - Andrew A. House
- Departments of Medicine The University of Western Ontario, London, Ontario, Canada
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20
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du Plessis JP, Melse-Boonstra A, Zandberg L, Nienaber-Rousseau C. Gene interactions observed with the HDL-c blood lipid, intakes of protein, sugar and biotin in relation to circulating homocysteine concentrations in a group of black South Africans. Mol Genet Metab Rep 2019; 22:100556. [PMID: 31908954 PMCID: PMC6938949 DOI: 10.1016/j.ymgmr.2019.100556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/05/2019] [Accepted: 12/12/2019] [Indexed: 11/18/2022] Open
Abstract
Background Elevated homocysteine (Hcy) is associated with several pathologies. Gene–diet interactions related to Hcy might be used to customize dietary advice to reduce disease incidence. To explore this possibility, we investigated interactions between anthropometry, biochemical markers and diet and single-nucleotide polymorphisms (SNPs) in relation to Hcy concentrations. Five SNPs of Hcy-metabolizing enzymes were analyzed in 2010 black South Africans. Results Hcy was higher with each additional methylenetetrahydrofolate reductase (MTHFR) C677T minor allele copy, but was lower in methionine synthase (MTR) 2756AA homozygotes than heterozygotes. Individuals harboring cystathionine β synthase (CBS) 833 T/844ins68 had lower Hcy concentrations than others. No interactive effects were observed with any of the anthropometrical markers. MTHFR C677T and CBS T833C/844ins68 homozygote minor allele carriers presented with lower Hcy as high density lipoprotein cholesterol (HDL-c) increased. Hcy concentrations were negatively associated with dietary protein and animal protein intake in the TT and TC genotypes, but positively in the CC genotype of CBS T833C/844ins68. Hcy was markedly higher in TT homozygotes of MTHFR C677T as added sugar intake increased. In CBS T833C/844ins68 major allele carriers, biotin intake was negatively associated with Hcy; but positively in those harboring the homozygous minor allele. Conclusions The Hcy–SNP associations are modulated by diet and open up the possibility of invoking dietary interventions to treat hyperhomocysteinemia. Future intervention trials should further explore the observed gene–diet and gene–blood lipid interactions.
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Key Words
- %TCHO, percentage total carbohydrate intake
- %TE, percentage of total energy
- A, adenine
- Ala, alanine
- Asp, aspartic acid
- Biotin
- Blood lipid–gene interactions
- C, cytosine
- CBS, cystathionine β synthase
- CI, confidence intervals
- CV, coefficient variation
- ES, effect size
- G, guanine
- GGT, gamma glutamyl transferase
- GLM, generalized linear model
- Gene–diet interactions
- Gly, glycine
- HDL-c, high-density lipoprotein cholesterol
- HHcy, hyperhomocysteinemia
- HW, Hardy Weinberg
- HWE, Hardy–Weinberg equilibrium
- HbA1c, glycated hemoglobin
- Hcy, homocysteine
- Hyperhomocysteinemia
- ID, identity
- ISAK, International Society for the Advancement of Kinanthropometry
- Ile, isoleucine
- LD, pairwise linkage-disequilibrium
- LDL-c, low density lipoprotein cholesterol
- MAF, minor allele frequency
- MRC, Medical Research Council
- MT, mutant type
- MTHFR, methylenetetrahydrofolate reductase
- MTR, methionine synthase
- Nutrient–gene interactions
- Nutrigenetics
- PA, physical activity
- PCR, polymerase chain reaction
- PURE, Prospective Urban and Rural Epidemiology
- Precision nutrition
- Protein
- QFFQ, quantitative food frequency questionnaire
- RFLP, restriction fragment length polymorphism
- SD, standard deviations
- SE, standard error
- SFA, saturated fatty acids
- SNP, single-nucleotide polymorphism
- Sugar
- T, thymine
- THUSA, Transition and Health during Urbanization in South Africa
- Thr, threonine
- Total homocysteine
- Val, valine
- WT, wild type.
- bp, base pairs
- d, Cohen's d-value
- ins, insertion
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Affiliation(s)
- Jacomina P du Plessis
- Centre of Excellence for Nutrition, North-West University, Private bag X6001, Nutrition, Box 594, Potchefstroom 2520, South Africa
| | - Alida Melse-Boonstra
- Centre of Excellence for Nutrition, North-West University, Private bag X6001, Nutrition, Box 594, Potchefstroom 2520, South Africa.,Division of Human Nutrition and Health, Wageningen University & Research, P.O. Box 9101, 6700 HB Wageningen, The Netherlands
| | - Lizelle Zandberg
- Centre of Excellence for Nutrition, North-West University, Private bag X6001, Nutrition, Box 594, Potchefstroom 2520, South Africa
| | - Cornelie Nienaber-Rousseau
- Centre of Excellence for Nutrition, North-West University, Private bag X6001, Nutrition, Box 594, Potchefstroom 2520, South Africa
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21
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Ramuš SM, Petrovič D. Genetic Variations and Subclinical Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus. Curr Vasc Pharmacol 2018; 17:16-24. [DOI: 10.2174/1570161116666180206112635] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 09/19/2017] [Accepted: 11/07/2017] [Indexed: 12/18/2022]
Abstract
Atherosclerosis and its cardiovascular complications are the main cause of death in diabetic
patients. Patients with diabetes mellitus have a greater than 10-fold risk of cardiovascular disease in
their lifetime. The carotid Intima-Media Thickness (cIMT), a surrogate marker for the presence and
progression of atherosclerosis, predicts future cardiovascular events in asymptomatic subjects with Type
2 Diabetes Mellitus (T2DM). This review focuses on genetic variants that contribute to the pathobiology
of subclinical atherosclerosis in the setting of T2DM. Specifically, we devoted our attention to wellstudied
genes selected for their relevance for atherosclerosis. These include: The Renin-Angiotensin-
Aldosterone System (RAAS), Apolipoprotein E (ApoE), Methylenetetrahydrofolate Reductase (MTHFR)
and pro-inflammatory genes.
</P><P>
The ever-growing availability of advanced genotyping technologies has made Genome-Wide Association
Studies (GWAS) possible. Although several bioinformatics tools have been developed to manage
and interpret the huge amounts of data produced, there has been limited success in the many attempts to
uncover the biological meaning of the novel susceptibility loci for atherosclerosis.
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Affiliation(s)
- Sara Mankoč Ramuš
- Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Daniel Petrovič
- Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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22
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Shute C. A case report of branch retinal artery occlusion in a teenager due to hyperhomocysteinaemia; the interplay of genetic and nutritional defects. BMC Ophthalmol 2018; 18:220. [PMID: 30255822 PMCID: PMC6156839 DOI: 10.1186/s12886-018-0859-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Background Retinal vascular occlusions are uncommon in young people and require more in-depth investigation into the cause. Studies have revealed that a high level of circulating homocysteine poses a risk for retinal vaso-occlusive events across a wide age range. This case report reflects on how the interplay of genetic mutation and vitamin deficiency can cause a pathological level of homocysteine with resultant branch retinal artery occlusion in a young patient. Case presentation A 16-year-old boy presented to eye casualty with acute inferior visual field loss in the left eye. Visual acuity remained normal at 6/6 each eye and the event was painless. Initial assessment, and retinal photography revealed a left superior hemi-field branch retinal artery occlusion with macular sparing. Given the patient’s age, extensive investigation into the cause was carried out. Positive findings were of an elevated level of homocysteine as a result of vitamin B12 and folic acid deficiency as well as a genetic mutation in the MTHFR gene (encoding MTHFR enzyme which is vital in normal homocysteine metabolism). Vitamin B12 and folic acid were replaced which in turn normalized the patient’s homocysteine levels. At two months, the patient’s visual fields had also improved, and no further vascular event had occurred. Conclusions This case report has highlighted the link between hyperhomocysteinaemia and retinal artery occlusion. However, despite vitamin replacement being shown to normalize homocysteine levels, no evidence exists to date as to whether this will reduce the risk of further retinal vascular occlusion.
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Affiliation(s)
- Clare Shute
- Royal Victoria Hospital, Belfast, Northern Ireland.
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23
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Yuyun MF, Ng LL, Ng GA. Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy? Microvasc Res 2018; 119:7-12. [PMID: 29596860 DOI: 10.1016/j.mvr.2018.03.012] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 12/23/2017] [Accepted: 03/24/2018] [Indexed: 12/16/2022]
Abstract
Homeostasis around vascular endothelium is a function of the equilibrium between the bioavailability of nitric oxide (NO) and oxidizing reactive oxygen species (ROS). Within the vascular endothelium, NO enhances vasodilatation, reduces platelet aggression and adhesion (anti-thrombotic), prevents smooth muscle proliferation, inhibits adhesion of leukocytes and expression of pro-inflammatory cytokines genes (anti-inflammatory), and counters the oxidation of low density lipoprotein (LDL) cholesterol. A shift in the equilibrium that favours NO deficiency and ROS formation leads to endothelial dysfunction and cardiovascular disease. The synthesis of NO is catalysed by nitric oxide synthase and co-factored by tetrahydrobiopterin (BH4), nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), and flavin mononucleotide (FMN). The focus of this review is on endothelial nitric oxide synthase (eNOS), although we recognize that the other nitric oxide synthases may contribute as well. Levels of homocysteine and the active metabolite of folate, 5-methyltetrahydrofolate (5-MTHF), play a determining role in circulating levels of nitric oxide. We review endothelial nitric oxide bioavailabilty in relation to endothelial dysfunction as well as the therapeutic strategies involving the nitric oxide synthesis pathway. Although folate supplementation improves endothelial function, results from large clinical trials and meta-analyses on palpable clinical endpoints have been inconsistent. There are however, encouraging results from animal and clinical studies of supplementation with the co-factor for nitric oxide synthesis, BH4, though its tendency to be oxidized to dihydrobiopterin (BH2) remains problematic. Understanding how to maintain a high ratio of BH4 to BH2 appears to be the key that will likely unlock the therapeutic potential of nitric oxide synthesis pathway.
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Affiliation(s)
- Matthew F Yuyun
- Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK; The Landsman Heart and Vascular Center, Cardiovascular Medicine, Lahey Hospital & Medical Center, 41 Burlington Mall Road, Burlington, MA 01805, USA; Tufts University School of Medicine, 145 Harrison Avenue, Boston, MA 02111, USA.
| | - Leong L Ng
- Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK; National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK
| | - G André Ng
- Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK; National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK
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24
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Hankey GJ. B vitamins for stroke prevention. Stroke Vasc Neurol 2018; 3:51-58. [PMID: 30022794 PMCID: PMC6047336 DOI: 10.1136/svn-2018-000156] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 05/11/2018] [Accepted: 05/11/2018] [Indexed: 12/24/2022] Open
Abstract
Supplementation with B vitamins (vitamin B9(folic acid), vitamin B12 and vitamin B6) lowers blood total homocysteine (tHcy) concentrations by about 25% and reduces the relative risk of stroke overall by about 10% (risk ratio (RR) 0.90, 95% CI 0.82 to 0.99) compared with placebo. Homocysteine-lowering interventions have no significant effect on myocardial infarction, death from any cause or adverse outcomes. Factors that appear to modify the effect of B vitamins on stroke risk include low folic acid status, high tHcy, high cyanocobalamin dose in patients with impaired renal function and concurrent antiplatelet therapy. In regions with increasing levels or established policies of population folate supplementation, evidence from observational genetic epidemiological studies and randomised controlled clinical trials is concordant in suggesting an absence of benefit from lowering of homocysteine with folic acid for prevention of stroke. Clinical trials indicate that in countries which mandate folic acid fortification of food, folic acid supplementation has no significant effect on reducing stroke risk (RR 1.05, 95% CI 0.90 to 1.23). However, in countries without mandatory folic acid food fortification, folic acid supplementation reduces the risk of stroke by about 15% (RR 0.85, 95% CI 0.77 to 0.94). Folic acid alone or in combination with minimal cyanocobalamin (≤0.05 mg/day) is associated with an even greater reduction in risk of future stroke by 25% (RR 0.75, 95% CI 0.66 to 0.86), whereas the combination of folic acid and a higher dose of cyanocobalamin (≥0.4 mg/day) is not associated with a reduced risk of future stroke (RR 0.95, 95% CI 0.86 to 1.05). The lack of benefit of folic acid plus higher doses of cyanocobalamin (≥0.4 mg/day) was observed in trials which all included participants with chronic kidney disease. Because metabolic B12 deficiency is very common and usually not diagnosed, future randomised trials of homocysteine-lowering interventions for stroke prevention should probably test a combination of folic acid and methylcobalamin or hydroxocobalamin instead of cyanocobalamin, and perhaps vitamin B6.
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Affiliation(s)
- Graeme J Hankey
- UWA Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia.,Department of Neurology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
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25
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Fezeu LK, Ducros V, Guéant JL, Guilland JC, Andreeva VA, Hercberg S, Galan P. MTHFR 677C → T genotype modulates the effect of a 5-year supplementation with B-vitamins on homocysteine concentration: The SU.FOL.OM3 randomized controlled trial. PLoS One 2018; 13:e0193352. [PMID: 29813097 PMCID: PMC5973566 DOI: 10.1371/journal.pone.0193352] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 01/31/2018] [Indexed: 01/25/2023] Open
Abstract
AIMS To study how MTHFR 677C→T genotype modulates the effect of supplementation with B-vitamins on total homocysteine (tHcy) and B-vitamin concentrations. METHODS 2381 patients with a personal history of cardiovascular disease were randomly assigned to one of four groups: 1) B-vitamins alone (560 μg of 5-methyl-THF, 3 mg of vitamin B6 and 20 μg of vitamin B12), 2) n-3 fatty acids alone (600 mg of EPA and DHA in a 2:1 ratio), 3) B-vitamins and n-3 fatty acids, and 4) placebo. Participants were followed up for 4.7 years. At baseline and annually thereafter, biological parameters were assessed. Multivariate and linear mixed models were fit to study the interaction between B-vitamins and MTHFR genotype. RESULTS Among supplemented participants, concentrations of all three B-vitamins increased during the first year (all p<0.0001) across MTHFR genotype categories. tHcy decreased by 26.3% during the first year (p<0.0001), then steadily increased throughout the 5 years (ptrend<0.001). However, at the end of follow-up, that increase was smaller among TT than among CT or CC subjects (pinteraction<0.02). At baseline, the difference in tHcy concentrations between TT homozygous and CC homozygous subjects was 2.33 μmol/l (p<0.001). After 5 years, that difference was reduced to 1.06 μmol/l and remained statistically significant (p<0.001). CONCLUSION Participants with the TT genotype exhibited a lower 5-year decrease in tHcy concentrations following a B-vitamin supplementation than did participants with the CC or CT genotype. CLINICAL TRIAL REGISTRATION Current Controlled Trials # ISRCTN41926726.
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Affiliation(s)
- Leopold K. Fezeu
- Université Paris 13, Equipe de Recherche en Epidémiologie Nutritionnelle (EREN), Centre de Recherche en Epidémiologie et Statistiques, Inserm (U1153), Inra (U1125), Cnam, COMUE Sorbonne Paris Cité, Bobigny, France
- * E-mail:
| | - Veronique Ducros
- Département de Biochimie Pharmacologie et Toxicologie, UM Biochimie Nutritionnelle et Hormonale, Institut de Biologie et Pathologie, Centre Hospitalier Universitaire, Grenoble, France
| | - Jean-Louis Guéant
- Inserm U724, Pathologies Cellulaire et Moléculaire en Nutrition, Faculté de Médecine, Université Henry Poincaré, Vandoeuvre lès Nancy, France
| | | | - Valentina A. Andreeva
- Université Paris 13, Equipe de Recherche en Epidémiologie Nutritionnelle (EREN), Centre de Recherche en Epidémiologie et Statistiques, Inserm (U1153), Inra (U1125), Cnam, COMUE Sorbonne Paris Cité, Bobigny, France
| | - Serge Hercberg
- Université Paris 13, Equipe de Recherche en Epidémiologie Nutritionnelle (EREN), Centre de Recherche en Epidémiologie et Statistiques, Inserm (U1153), Inra (U1125), Cnam, COMUE Sorbonne Paris Cité, Bobigny, France
- Département de Santé Publique, Hôpital Avicenne, Bobigny, France
| | - Pilar Galan
- Université Paris 13, Equipe de Recherche en Epidémiologie Nutritionnelle (EREN), Centre de Recherche en Epidémiologie et Statistiques, Inserm (U1153), Inra (U1125), Cnam, COMUE Sorbonne Paris Cité, Bobigny, France
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Pařízková M, Andel R, Lerch O, Marková H, Gažová I, Vyhnálek M, Hort J, Laczó J. Homocysteine and Real-Space Navigation Performance among Non-Demented Older Adults. J Alzheimers Dis 2018; 55:951-964. [PMID: 27802238 DOI: 10.3233/jad-160667] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND High plasma homocysteine (Hcy) level is related to higher risk of Alzheimer's disease (AD) and lower cognitive performance in older adults. OBJECTIVE To assess the association between plasma Hcy level and real-space navigation performance and the role of vascular risk and protective factors, APOE status, and white matter lesions (WML) on this association. METHODS Ninety-two non-demented older adults (29 with amnestic mild cognitive impairment, 46 with subjective cognitive decline, and 17 cognitively normal older adults) underwent spatial navigation testing of egocentric, allocentric, and mixed navigation in a real-space analogue of the Morris water maze, neuropsychological examination, blood collection, and MRI brain scan with evaluation of WML. RESULTS In the regression analyses controlling for age, gender, education, and depressive symptoms, higher plasma Hcy level was related to worse mixed and egocentric (β= 0.31; p = 0.003 and β= 0.23; p = 0.017) but not allocentric (p > 0.05) navigation performance. Additional controlling for vascular risk and protective factors, WML, and APOE status did not modify the results. High total cholesterol and low vitamin B12 and folate levels increased the adverse effect of Hcy on egocentric and mixed navigation. WML did not explain the association between plasma Hcy level and navigation performance. CONCLUSION Elevated plasma Hcy level may affect real-space navigation performance above and beyond vascular brain changes. This association may be magnified in the presence of high total cholesterol and low folate or vitamin B12 levels. Attention to the level of plasma Hcy may be a viable intervention strategy to prevent decline in spatial navigation in non-demented older adults.
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Affiliation(s)
- Martina Pařízková
- Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic
| | - Ross Andel
- School of Aging Studies, University of South Florida, Tampa, FL, USA.,International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
| | - Ondřej Lerch
- Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
| | - Hana Marková
- Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
| | - Ivana Gažová
- Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
| | - Martin Vyhnálek
- Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
| | - Jakub Hort
- Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
| | - Jan Laczó
- Memory Clinic, Department of Neurology, Charles University, 2nd Faculty of Medicine and Motol University Hospital, Prague, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
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Escobedo J, Paz-Aragón E, Vega-Rodríguez LH, Benítez Sanfeliz MA, Estrada-Rodríguez H, González-Figueroa E, Liceaga-Craviotto MG, Gutiérrez-Cuevas J, Valladares-Salgado A, Cruz M. The Methylenetetrahydrofolate Reductase C677T (rs1801133) and Apolipoprotein A5-1131T>C (rs662799) Polymorphisms, and Anemia Are Independent Risk Factors for Ischemic Stroke. J Stroke Cerebrovasc Dis 2018; 27:1357-1362. [PMID: 29398535 DOI: 10.1016/j.jstrokecerebrovasdis.2017.12.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 11/21/2017] [Accepted: 12/19/2017] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND Although there is adequate knowledge as to the role of traditional cardiovascular risk factors on stroke incidence, knowledge of other risk factors, particularly genetic ones, is still incomplete. METHODS To assess the participation of some polymorphisms, along with other modifiable risk factors, a case-control study was conducted. A total of 253 cases were identified in the emergency room of a general regional hospital, with a clinical trait of stroke confirmed by a skull computerized axial tomography scan. In the surgery ward, 253 controls were identified, gender and age (±5 years) matched. Biochemical parameters were measured, and 4 polymorphisms were genotyped by polymerase chain reaction, rs1801133 (methylenetetrahydrofolate reductase [MTHFR]), rs1498373 (dimethylarginine dimethylaminohydrolase type 1 [DDAH1]), rs662799 (apolipoprotein A5 [APOA5]), and rs1799983 (endothelial nitric oxide). Odds ratios were estimated to assess the strength of association, with 95% confidence intervals, both in a matched case-control analysis and in a conditional regression analysis. RESULTS Cases had higher mean blood pressure and triglycerides and lower hemoglobin levels. Heterozygous and homozygous subjects to the rs1801133 variant of the MTHFR gene had a 3-fold higher risk of stroke. In the dominant model, those with the polymorphism rs662799 of the promoter region for APOA5 had twice the risk of stroke. Anemia increased the risk of stroke 4-fold. CONCLUSIONS Polymorphisms of the genes MTHFR (rs1801133) and APOA5 (rs662799), as well as anemia, are independent risk factors for stroke in Mexicans, together with traditional cardiovascular risk factors such as high triglycerides and high blood pressure.
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Affiliation(s)
- Jorge Escobedo
- Unidad de Investigación en Epidemiología Clínica, Hospital Regional 1, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico; Internal Medicine Department, Hospital General Regional No. 1. IMSS, Mexico City, Mexico.
| | - Emmanuel Paz-Aragón
- Unidad de Investigación en Epidemiología Clínica, Hospital Regional 1, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico; Internal Medicine Department, Hospital General Regional No. 1. IMSS, Mexico City, Mexico
| | - Luz Helena Vega-Rodríguez
- Unidad de Investigación en Epidemiología Clínica, Hospital Regional 1, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico; Internal Medicine Department, Hospital General Regional No. 1. IMSS, Mexico City, Mexico
| | - Miguel Alejandro Benítez Sanfeliz
- Unidad de Investigación en Epidemiología Clínica, Hospital Regional 1, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico; Internal Medicine Department, Hospital General Regional No. 1. IMSS, Mexico City, Mexico
| | - Humberto Estrada-Rodríguez
- Unidad de Investigación en Epidemiología Clínica, Hospital Regional 1, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico; Internal Medicine Department, Hospital General Regional No. 1. IMSS, Mexico City, Mexico
| | - Evangelina González-Figueroa
- Unidad de Investigación en Epidemiología Clínica, Hospital Regional 1, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | | | - Jorge Gutiérrez-Cuevas
- Unidad de Investigación en Epidemiología Clínica, Hospital Regional 1, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico
| | - Adán Valladares-Salgado
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Miguel Cruz
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
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Liu F, Silva D, Malone MV, Seetharaman K. MTHFR A1298C and C677T Polymorphisms Are Associated with Increased Risk of Venous Thromboembolism: A Retrospective Chart Review Study. Acta Haematol 2017; 138:208-215. [PMID: 29212064 DOI: 10.1159/000480447] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 08/21/2017] [Indexed: 11/19/2022]
Abstract
BACKGROUND Methylene tetrahydrofolate reductase (MTHFR) is a key enzyme in homocysteine metabolism. This study aims to determine the impact of MTHFR polymorphisms on plasma homocysteine levels and risks of venous thromboembolism (VTE). METHODS This retrospective chart review study included a total of 188 subjects who were tested for MTHFR polymorphisms at Metrowest Coagulation Laboratory between April 2011 and April 2016. Two independent coders were trained to extract relevant clinical data for statistical analysis. RESULTS VTE occurred in 50% of patients with compound mutation, compared with only 28.6% of subjects from the wild-type group. Patients with heterozygous or homozygous A1298C or C677T variants had an intermediate risk of VTE. The median homocysteine level in the wild-type group was slightly lower than that of heterozygous or homozygous MTHFR variants. The difference, however, was not significant (p = 0.6193). Moreover, there was no difference in plasma homocysteine level between patients with VTE versus VTE-free (p = 0.4923). CONCLUSIONS Heterozygous or homozygous MTHFR variants, especially a compound mutation, are associated with increased risk of VTE. Hyperhomocysteinemia does not correlate with MTHFR polymorphisms or VTE risk. Hence, MTHFR genotyping provides more consistent assessment of VTE risk. This information can be incorporated into risk stratification for early intervention and prophylaxis of VTE.
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Affiliation(s)
- Fang Liu
- Metrowest Medical Center, Framingham, MA, USA
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29
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Franchini M, Martinelli I, Mannucci PM. Uncertain thrombophilia markers. Thromb Haemost 2017; 115:25-30. [DOI: 10.1160/th15-06-0478] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 07/03/2015] [Indexed: 11/05/2022]
Abstract
SummaryThe development of venous thromboembolism (VTE), which includes deep-vein thrombosis and pulmonary embolism, may be associated with inherited or acquired risk factors that can be measured in plasma or DNA testing. The main inherited thrombophilias include the plasma deficiencies of the natural anticoagulants antithrombin, protein C and S; the gain-of-function mutations factor V Leiden and prothrombin G20210A; some dysfibrinogenaemias and high plasma levels of coagulation factor VIII. Besides these established biomarkers, which usually represent the first-level laboratory tests for thrombophilia screening, a number of additional abnormalities have been less consistently associated with an increased VTE risk. These uncertain causes of thrombophilias will be discussed in this narrative review, focusing on their clinical impact and the underlying pathogenetic mechanisms. Currently, there is insufficient ground to recommend their inclusion within the framework of conventional thrombophilia testing.
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30
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Garcia Lopez M, Bønaa KH, Ebbing M, Eriksen EF, Gjesdal CG, Nygård O, Tell GS, Ueland PM, Meyer HE. B Vitamins and Hip Fracture: Secondary Analyses and Extended Follow-Up of Two Large Randomized Controlled Trials. J Bone Miner Res 2017; 32:1981-1989. [PMID: 28574605 DOI: 10.1002/jbmr.3189] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 05/23/2017] [Accepted: 05/31/2017] [Indexed: 12/14/2022]
Abstract
Elevated plasma homocysteine levels are associated with increased risk of fractures in observational studies. However, it is unsettled whether homocysteine-lowering treatment affects fracture risk. The aim of this study was to investigate the effect of an intervention with B vitamins on the risk of hip fracture in a secondary analysis of combined data from two large randomized controlled trials originally designed to study cardiovascular diseases. Both trials had identical design, intervention, and primary objective. Based on a two-by-two factorial design, the intervention consisted of a daily capsule with either (1) folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg); (2) folic acid (0.8 mg) plus vitamin B12 (0.4 mg); (3) vitamin B6 alone (40 mg); or (4) placebo. The participants were followed with respect to hip fracture during the trial or during an extended follow-up (from the trial start for each patient until the end of 2012). No statistically significant association was found between folic acid plus vitamin B12 treatment and the risk of hip fracture, neither during the trial (median 3.3 years; hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.48 to 1.59) nor during the extended follow-up (median 11.1 years; HR 1.08; 95% CI, 0.84 to 1.40). Nor were there significant differences in the risk of hip fracture between groups receiving versus not receiving vitamin B6 during the trial (HR 1.42; 95% CI, 0.78 to 2.61). However, during the extended follow-up, those receiving vitamin B6 showed a significant 42% higher risk of hip fracture (HR 1.42; 95% CI, 1.09 to 1.83) compared to those not receiving vitamin B6 . In conclusion, treatment with folic acid plus vitamin B12 was not associated with the risk of hip fracture. Treatment with a high dose of vitamin B6 was associated with a slightly increased risk of hip fracture during the extended follow-up (in-trial plus post-trial follow-up). © 2017 American Society for Bone and Mineral Research.
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Affiliation(s)
- Maria Garcia Lopez
- Department of Clinical Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.,Department of Community Medicine, Institute of Health and Society, University of Oslo, Norway
| | - Kaare H Bønaa
- Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway.,Clinic for Heart Disease, St. Olav's University Hospital, Trondheim, Norway.,Department of Community Medicine, The Arctic University of Norway (UiT), Tromsø, Norway
| | - Marta Ebbing
- Domain for Health Data and Digitalization, Norwegian Institute of Public Health, Bergen, Norway.,Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
| | - Erik F Eriksen
- Department of Clinical Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
| | - Clara G Gjesdal
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Rheumatology, Haukeland University Hospital, Bergen, Norway
| | - Ottar Nygård
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Heart Disease, Haukeland University Hospital, Bergen, Norway
| | - Grethe S Tell
- Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
| | - Per M Ueland
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway
| | - Haakon E Meyer
- Department of Community Medicine, Institute of Health and Society, University of Oslo, Norway.,Domain for Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway
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31
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Robeva R, Tanev D, Andonova S, Nikolova M, Tomova A, Kumanov P, Savov A, Rashkov R, Kolarov Z. Inherited Thrombophilias Could Influence the Reproductive Outcome in Women with Systemic Lupus Erythematosus. Balkan J Med Genet 2017; 20:21-26. [PMID: 28924537 PMCID: PMC5596818 DOI: 10.1515/bjmg-2017-0011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease associated with different reproductive complications in the affected women. Inherited thrombophilias are genetic factors increasing the risk for thromboembolism and recurrent pregnancy loss, but their influence on other reproductive disturbances in SLE patients has not been completely clarified. Two hundred and twenty-three Caucasian women (112 with SLE and 111 controls) were included in the study. Complete reproductive history of all SLE patients was carefully obtained. Genotyping for the FVLeiden, FIIG20210A, and MTHFRC677T polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No significant differences in the prevalence of the FVLeiden, FIIG20210A, and MTHFRC677T polymorphisms between patients and controls were established. Patients with FVLeiden had fewer pregnancies (0.57 ± 0.98 vs. 2.18 ± 1.58; p = 0.007) than the others, while no significant differences in the reproductive history of FIIG20210A carriers and non-carriers were observed (p >0.05). In the SLE group, 41.67% of women with the MTHFRC677T TT genotype had at least one miscarriage in comparison to only 14.00% of the other female patients (p = 0.030). While the prevalence of the investigated thrombophilias was similar in patients with SLE and healthy women, a substantial influence of the inherited prothrombotic factors on the reproductive history of patients was revealed. The investigations of the FVLeiden and MTHFRC677T polymorphisms in SLE patients could help to identify women at highest risk for reproductive failure and thus, further studies in other ethnic groups would be of strong clinical importance.
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Affiliation(s)
- R Robeva
- Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Medical Faculty, Sofia, Bulgaria
| | - D Tanev
- Clinic of Rheumatology, Medical University, Sofia, Medical Faculty, Sofia, Bulgaria
| | - S Andonova
- National Genetic Laboratory, University Specialized Hospital for Active Treatment in Obstetrics and Gynecology, "Maichin dom", Medical University, Sofia, Medical Faculty, Sofia, Bulgaria
| | - M Nikolova
- Clinic of Nephrology, Medical University, Sofia, Medical Faculty, Sofia, Bulgaria
| | - A Tomova
- Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Medical Faculty, Sofia, Bulgaria
| | - Ph Kumanov
- Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Medical Faculty, Sofia, Bulgaria
| | - A Savov
- National Genetic Laboratory, University Specialized Hospital for Active Treatment in Obstetrics and Gynecology, "Maichin dom", Medical University, Sofia, Medical Faculty, Sofia, Bulgaria
| | - R Rashkov
- Clinic of Rheumatology, Medical University, Sofia, Medical Faculty, Sofia, Bulgaria
| | - Zl Kolarov
- Clinic of Rheumatology, Medical University, Sofia, Medical Faculty, Sofia, Bulgaria
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32
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Kandaz C, Önal B, Özen D, Demir B, Akkan AG, Özyazgan S. Investigation of MTHFR gene C677T polymorphism in cardiac syndrome X patients. J Clin Lab Anal 2017; 32. [PMID: 28481466 DOI: 10.1002/jcla.22247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 03/31/2017] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Definition of Cardiac Syndrome X (CSX) refers to groups of patients with positive exercise stress test and normal epicardial coronary arteries on coronary angiography accompanied by chest pain. Although the etiology of CSX is not completely understood, there is a common consensus that its pathophysiology may be associated with endothelial dysfunction resulting in impaired coronary flow. Some polymorphisms observed on the MTHFR gene cause inactivation of the MTHFR enzyme, leading to hyperhomocysteinemia and homocysteinuria, which are prominent risk factors of cardiovascular and cerebrovascular diseases. It was aimed to explain the association of the endothelial dysfunction, which is thought to play a role in the pathophysiology of CSX, with C677T polymorphism on MTHFR gene based on genetic basis. METHODS A total of 176 CSX patients and 196 healthy subjects with similar age and clinical features were compared in terms of C677T polymorphism of the MTHFR gene. RESULTS AND CONCLUSION There was no significant difference in terms of MTHFR gene C677T polymorphism between CSX patients and controls. When genotypic distribution was compared based on gender in both patients and controls, no significant difference was found between male and female subjects (P>.05). As fasting blood sugar and urea values were significantly higher, alanine aminotransferase and gamma-glutamyl transferase levels were significantly lower in the patients than the controls (P<.05). Described family story of the patients was significantly higher than the controls (P<.05). These suggest that homocysteine metabolism in CSX is not directly related to the endothelial dysfunction and thus the effect on the microvascular circulation.
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Affiliation(s)
- Cemre Kandaz
- Department of Medical Pharmacology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Burak Önal
- Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Istinye University, Istanbul, Turkey
| | - Deniz Özen
- Department of Medical Pharmacology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Bülent Demir
- Department of Cardiology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey
| | - A Gökhan Akkan
- Department of Medical Pharmacology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Sibel Özyazgan
- Department of Medical Pharmacology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver conditions that are characterized by steatosis, inflammation, fibrosis, and liver injury. The global prevalence of NAFLD is rapidly increasing in proportion to the rising incidence of obesity and type 2 diabetes. Because NAFLD is a multifaceted disorder with many underlying metabolic abnormalities, currently, there is no pharmacological agent that is therapeutically approved for the treatment of this disease. Folate is a water-soluble B vitamin that plays an essential role in one-carbon transfer reactions involved in nucleic acid biosynthesis, methylation reactions, and sulfur-containing amino acid metabolism. The liver is the primary organ responsible for storage and metabolism of folates. Low serum folate levels have been observed in patients with obesity and diabetes. It has been reported that a low level of endogenous folates in rodents perturbs folate-dependent one-carbon metabolism, and may be associated with development of metabolic diseases such as NAFLD. This review highlights the biological role of folate in the progression of NAFLD and its associated metabolic complications including obesity and type 2 diabetes. Understanding the role of folate in metabolic disease may position this vitamin as a potential therapeutic for NAFLD.
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Affiliation(s)
- Victoria Sid
- a St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada.,b Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Yaw L Siow
- a St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada.,b Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.,c Agriculture and Agri-Food Canada, Winnipeg, MB R3C 1B2, Canada
| | - Karmin O
- a St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada.,b Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.,d Department of Animal Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
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Xu B, Kong X, Xu R, Song Y, Liu L, Zhou Z, Gu R, Shi X, Zhao M, Huang X, He M, Fu J, Cai Y, Li P, Cheng X, Wu C, Chen F, Zhang Y, Tang G, Qin X, Wang B, Xue H, Chen Y, Tian Y, Sun N, Cui Y, Hou FF, Li J, Huo Y. Homocysteine and all-cause mortality in hypertensive adults without pre-existing cardiovascular conditions: Effect modification by MTHFR C677T polymorphism. Medicine (Baltimore) 2017; 96:e5862. [PMID: 28225483 PMCID: PMC5569412 DOI: 10.1097/md.0000000000005862] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Previous studies support an association between elevated total homocysteine (tHcy) levels and increased all-cause mortality. However, few prospective studies have examined this association in hypertensive patients, and/or tested any effect modification by the methylene tetrahydrofolate reductase (MTHFR) C677T genotype. METHODS This was a post hoc analysis of the China Stroke Primary Prevention Trial. Serum tHcy and folate were measured at baseline. Individual MTHFR C677T genotype (CC, CT, and TT) was determined. Evidence for death included death certificates or home visits. Cumulative hazards of all-cause mortality by tHcy quartiles were estimated using the Kaplan-Meier method, and group differences were compared by log-rank tests. Hazard ratios (HRs) and 95% confidence intervals were estimated by Cox proportional-hazard regression models, adjusting for age, sex, baseline folate, vitamin B12, blood pressure, body mass index, smoking and alcohol drinking status, study center, total cholesterol, triglycerides, high-density lipoprotein cholesterol, fasting glucose, creatinine, and treatment group. Potential effect modification by the MTHFR genotype on the relationship between tHcy and all-cause mortality was tested. RESULTS The analyses included 20,424 hypertensive patients (41% males) without a history of myocardial infarction or stroke. Baseline mean age (SD) was 60 ± 7.5 years and mean (SD) serum tHcy was 14.5 ± 8.4 μmol/L. After a mean follow-up period of 4.5 years, there were 612 (3%) all-cause deaths. Kaplan-Meier survival curves revealed a graded relationship between tHcy quartiles and all-cause mortality. The HRs, using the lowest quartile as the reference, were 1.2, 1.2, and 1.5 in Q2, Q3, and Q4, respectively. A linear trend test, using natural log-transformed tHcy, resulted in an HR of 1.5 (95% confidence interval 1.2-1.9, P < .001) after adjustment for lifestyle and health-related variables. Whereas the MTHFR genotype alone had little effect on mortality, it significantly modified the tHcy-mortality association, which was much stronger in the CC/CT genotype than in the TT genotype (P for interaction < 0.05). CONCLUSIONS Among Chinese hypertensive patients without cardiovascular comorbidities, elevated tHcy was a significant risk marker for death from all causes, and the association was subject to effect modification by MTHFR genotypes. If confirmed that tHcy and MTHFR genotypes may serve as useful biomarkers for mortality risk assessment and targeted intervention.
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Affiliation(s)
- Benjamin Xu
- Department of Cardiology, Peking University First Hospital, Beijing
| | - Xiangyi Kong
- Department of Cardiology, Peking University First Hospital, Beijing
| | - Richard Xu
- Department of Cardiology, Peking University First Hospital, Beijing
| | - Yun Song
- National Clinical Research Study Center for Kidney Disease; State Key Laboratory for Organ Failure Research; Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou
| | - Lishun Liu
- Institute for Biomedicine, Anhui Medical University
| | - Ziyi Zhou
- Institute for Biomedicine, Anhui Medical University
| | - Rui Gu
- Institute for Biomedicine, Anhui Medical University
| | - Xiuli Shi
- Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei
| | - Min Zhao
- National Clinical Research Study Center for Kidney Disease; State Key Laboratory for Organ Failure Research; Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou
| | - Xiao Huang
- Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Jiangxi
| | - Mingli He
- Department of Neurology, First People's Hospital, Lianyungang
| | - Jia Fu
- Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei
| | - Yefeng Cai
- Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou
| | - Ping Li
- Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Jiangxi
| | - Xiaoshu Cheng
- Department of Cardiology, the Second Affiliated Hospital of Nanchang University, Jiangxi
| | - Changyan Wu
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing
| | - Fang Chen
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing
| | - Yan Zhang
- Department of Cardiology, Peking University First Hospital, Beijing
| | - Genfu Tang
- School of Health Administration, Anhui Medical University, Hefei
| | - Xianhui Qin
- National Clinical Research Study Center for Kidney Disease; State Key Laboratory for Organ Failure Research; Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou
| | - Binyan Wang
- National Clinical Research Study Center for Kidney Disease; State Key Laboratory for Organ Failure Research; Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou
| | - Hao Xue
- Department of Cardiology, Chinese People's Liberation Army General Hospital, Beijing
| | - Yundai Chen
- Department of Cardiology, Chinese People's Liberation Army General Hospital, Beijing
| | - Ye Tian
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin
| | - Ningling Sun
- Department of Cardiology, Peking University People's Hospital
| | - Yimin Cui
- Department of Pharmacy, Peking University First Hospital, Beijing, China
| | - Fan Fan Hou
- National Clinical Research Study Center for Kidney Disease; State Key Laboratory for Organ Failure Research; Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou
| | - Jianping Li
- Department of Cardiology, Peking University First Hospital, Beijing
| | - Yong Huo
- Department of Cardiology, Peking University First Hospital, Beijing
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Tsang RSM, Mather KA, Sachdev PS, Reppermund S. Systematic review and meta-analysis of genetic studies of late-life depression. Neurosci Biobehav Rev 2017; 75:129-139. [PMID: 28137459 DOI: 10.1016/j.neubiorev.2017.01.028] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 01/23/2017] [Indexed: 11/15/2022]
Abstract
Late-life depression (LLD) is thought to be multifactorial in etiology, including a significant genetic component. While a number of candidate gene studies have been carried out, results remain inconclusive. We undertook a systematic review of all genetic association studies of depression or depressive symptoms in late life published before February 2016, and performed meta-analyses on polymorphisms investigated in three or more independent studies. A total of 46 candidate gene studies examining 56 polymorphisms in 23 genes as well as a genome-wide association study (GWAS) were included. Meta-analyses were conducted for four polymorphisms using random effects models, of which three (APOE, BDNF, SLC6A4) were associated with LLD. These genes are implicated in hippocampal plasticity and stress reactivity, suggesting that dysregulation of these pathways may contribute to LLD. Despite using a large sample, the only GWAS published to date identified only one genome-wide significant locus in the 5q21 region. In the future, larger genetic studies specifically examining LLD, including non-hypothesis-driven GWAS, are required to further identify genetic determinants of LLD.
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Affiliation(s)
- Ruby S M Tsang
- Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia.
| | - Karen A Mather
- Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia
| | - Perminder S Sachdev
- Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia; Neuropsychiatric Institute, Prince of Wales Hospital, Barker Street, Randwick, NSW, Australia
| | - Simone Reppermund
- Centre for Healthy Brain Ageing, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia; Department of Developmental Disability Neuropsychiatry, School of Psychiatry, UNSW Medicine, University of New South Wales, Sydney, Australia
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Aggarwal A, Srivastava S, Velmurugan M. Newer perspectives of coronary artery disease in young. World J Cardiol 2016; 8:728-734. [PMID: 28070240 PMCID: PMC5183972 DOI: 10.4330/wjc.v8.i12.728] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 10/03/2016] [Accepted: 11/02/2016] [Indexed: 02/06/2023] Open
Abstract
Coronary artery disease (CAD) occurring in less than 45 years of age is termed as young CAD. Recent studies show a prevalence of 1.2% of CAD cases in this age group. Ethnic wise south Asians especially Indians are more vulnerable to have CAD in young age group with a prevalence of 5% to 10%. Conventional risk factors such as smoking, diabetes, hypertension, obesity and family history seems to be as important as in older CAD subjects. But the prevalence of these risk factors seems to vary in younger subjects. By far the most commonly associated risk factor is smoking in young CAD. Several genes associated with lipoprotein metabolism are now found to be associated with young CAD like cholesterol ester transfer protein (CETP) gene, hepatic lipase gene, lipoprotein lipase gene, apo A1 gene, apo E gene and apo B. Biomarkers such as lipoprotein (a), fibrinogen, D-dimer, serum Wnt, gamma glutamyl transferase, vitamin D2 and osteocalcin are seems to be associated with premature CAD in some newer studies. In general CAD in young has better prognosis than older subjects. In terms of prognosis two risk factors obesity and current smoking are associated with poorer outcomes. Angiographic studies shows predominance of single vessel disease in young CAD patients. Like CAD in older person primary and secondary prevention plays an important role in prevention of new and further coronary events.
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Interactions between lifestyle and MTHFR polymorphisms on homocysteine concentrations in young adults belonging to the 1982 Pelotas Birth Cohort. Eur J Clin Nutr 2016; 71:259-266. [PMID: 27759072 DOI: 10.1038/ejcn.2016.193] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 08/05/2016] [Accepted: 08/12/2016] [Indexed: 11/08/2022]
Abstract
BACKGROUND/OBJECTIVES Homocysteine (Hcy) is a key intermediate in methionine metabolism. A high plasma concentration of Hcy is an independent risk factor for cardiovascular diseases among other determinants. In this study, we aimed to investigate the interactions between methylenetetrahydrofolate reductase enzyme gene (MTHFR) polymorphisms and lifestyle variables (smoking, alcohol intake and physical activity) on Hcy concentrations in a young Brazilian population. SUBJECTS/METHODS The study population comprised 3803 individuals from the Pelotas Birth Cohort, aged 22-23 years. Allelic discrimination assays and chemiluminescence immunoassays were performed for genotyping and serum Hcy measurements, respectively. Linear regression models were used to explore the effect of gene-lifestyle interactions on Hcy concentrations. RESULTS Men carrying the MTHFR 677TT genotype, who were also smokers and drinkers (⩾15 g of alcohol per day), had the highest concentration of Hcy (P-value for the interaction <0.001 for smoking and 0.002 for alcohol intake). In contrast, high folate concentrations attenuated the effects of the MTHFR C677T genotype on serum Hcy concentrations (P-value for interaction <0.001). Also, among males, blood folate concentration was the only lifestyle variable able to modify the influence of MTHFR A1298C genotypes on Hcy concentrations (P-value for the interaction <0.001). There was no strong evidence of an interaction between the MTHFR genotypes and the lifestyle variables in women. CONCLUSIONS In summary, our study demonstrates a sex difference in Hcy concentrations among Brazilian young adults regarding MTHFR C677T-lifestyle interactions that are worsened under conditions of low blood folate. Identification of potentially modifiable factors related to an increase in homocysteine in young adults, especially in those who are genetically susceptible, is important to prevent negative health consequences in the future.
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Association between methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and risk of ischemic stroke in North Indian population: A hospital based case–control study. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2016. [DOI: 10.1016/j.ejmhg.2016.01.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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Folate status, regulatory T cells and MTHFR C677T polymorphism study in allergic children. Adv Med Sci 2016; 61:300-305. [PMID: 27149557 DOI: 10.1016/j.advms.2016.03.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 03/01/2016] [Accepted: 03/30/2016] [Indexed: 12/22/2022]
Abstract
PURPOSE This study aimed to investigate early-life folate serum concentrations in children with food, inhalant or mixed type allergy. The influence of folate levels on the FoxP3 expression in Treg (regulatory T) cells in the studied children, taking into account the MTHFR (5,10-methylenetetrahydrofolate reductase) genotypes was also analyzed. MATERIAL AND METHODS The study was performed in 83 allergic children (study group) and 49 healthy children (control group), aged 2-72 months. Medical history of each child was obtained and laboratory tests (serum folic acid concentrations and MTHFR C677T polymorphism) were carried out. The percentage of Treg cells was evaluated in almost a half of the examined subjects (48.5%). RESULTS Significantly higher serum folate levels in the group of children with food allergy than in those with inhalant allergy was confirmed (P=0.037). In the study group the TT homozygotes were characterized by significantly lower folate concentrations than CC homozygotes (P=0.045). A negative correlation was demonstrated between the FoxP3 expression in CD4+CD25highFoxP3+ peripheral blood lymphocytes and serum folic acid concentrations. The correlation was more pronounced in the group of allergic children and it was statistically significant (r=-0.339, P<0.05). CONCLUSIONS The results of the study indicate a possibility of some effects of folate status on Treg cells, thus suggesting their potential role in the development and course of allergy in children.
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Rather RA, Dhawan V. Genetic markers: Potential candidates for cardiovascular disease. Int J Cardiol 2016; 220:914-23. [PMID: 27416153 DOI: 10.1016/j.ijcard.2016.06.251] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2016] [Revised: 06/22/2016] [Accepted: 06/26/2016] [Indexed: 02/07/2023]
Abstract
The effective prevention of cardiovascular disease depends upon the ability to recognize the high-risk individuals at an early stage of the disease or long before the development of adverse events. Evolving technologies in the fields of proteomics, metabolomics, and genomics have played a significant role in the discovery of cardiovascular biomarkers, but so far these methods have achieved the modest success. Hence, there is a crucial need for more reliable, suitable, and lasting diagnostic and therapeutic markers to screen the disease well in time to start the clinical aid to the patients. Gene polymorphisms associated with the cardiovascular disease play a decisive role in the disease onset. Therefore, the genetic marker evaluation to classify high-risk patients from low-risk patients trends an effective approach to patient management and care. Currently, there are no genetic markers available for extensive adoption as risk factors for coronary vascular disease, yet, there are numerous promising, biologically acceptable candidates. Many of these gene biomarkers, alone or in combination, can play an essential role in the prediction of cardiovascular risk. The present review highlights some putative emerging genetic biomarkers that could facilitate more authentic and fast diagnosis of CVD. This review also briefly describes few technological approaches employed in the biomarker search.
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Affiliation(s)
- Riyaz Ahmad Rather
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Veena Dhawan
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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Veeranki S, Gandhapudi SK, Tyagi SC. Interactions of hyperhomocysteinemia and T cell immunity in causation of hypertension. Can J Physiol Pharmacol 2016; 95:239-246. [PMID: 27398734 DOI: 10.1139/cjpp-2015-0568] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Although hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular diseases (CVD), there is a debate on whether HHcy is a risk factor or just a biomarker. Interestingly, homocysteine lowering strategies in humans had very little effect on reducing the cardiovascular risk, as compared with animals; this may suggest heterogeneity in human population and epigenetic alterations. Moreover, there are only few studies that suggest the idea that HHcy contributes to CVD in the presence of other risk factors such as inflammation, a known risk factor for CVD. Elevated levels of homocysteine have been shown to contribute to inflammation. Here, we highlight possible relationships between homocysteine, T cell immunity, and hypertension, and summarize the evidence that suggested these factors act together in increasing the risk for CVD. In light of this new evidence, we further propose that there is a need for evaluation of the causes of HHcy, defective remethylation or defective transsulfuration, which may differentially modulate hypertension progression, not just the homocysteine levels.
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Affiliation(s)
- Sudhakar Veeranki
- Department of Physiology and Biophysics, Health Sciences Centre, A-1216, School of Medicine, University of Louisville, 500 South Pres Street, Louisville, KY, 40202, USA.,Department of Physiology and Biophysics, Health Sciences Centre, A-1216, School of Medicine, University of Louisville, 500 South Pres Street, Louisville, KY, 40202, USA
| | - Siva K Gandhapudi
- Department of Physiology and Biophysics, Health Sciences Centre, A-1216, School of Medicine, University of Louisville, 500 South Pres Street, Louisville, KY, 40202, USA.,Department of Physiology and Biophysics, Health Sciences Centre, A-1216, School of Medicine, University of Louisville, 500 South Pres Street, Louisville, KY, 40202, USA
| | - Suresh C Tyagi
- Department of Physiology and Biophysics, Health Sciences Centre, A-1216, School of Medicine, University of Louisville, 500 South Pres Street, Louisville, KY, 40202, USA.,Department of Physiology and Biophysics, Health Sciences Centre, A-1216, School of Medicine, University of Louisville, 500 South Pres Street, Louisville, KY, 40202, USA
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Raina JK, Sharma M, Panjaliya RK, Bhagat M, Sharma R, Bakaya A, Kumar P. Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G gene polymorphisms and associated risk of cardiovascular diseases: A study from Jammu region. Indian Heart J 2016; 68:421-30. [PMID: 27316508 PMCID: PMC4912384 DOI: 10.1016/j.ihj.2016.02.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 01/12/2016] [Accepted: 02/07/2016] [Indexed: 02/07/2023] Open
Abstract
Aim Potent risk factors at both genetic and non-genetic levels are accountable for susceptibility and instigation of different cardiovascular phenotypes. Recently, homocysteine is being identified as an important predictor for cardiovascular diseases. Homocysteine remethylation plays a key role in the synthesis of methionine and S-adenosine methionine. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) genes are known to regulate the homocysteine remethylation reaction and higher homocysteine level is significantly associated with diverse cardiovascular phenotypes. In this context, we aimed to carry out a study on the association of MTHFR (C677T) and MTR (A2756G) gene polymorphism with CVD in population of Jammu region of J&K state. Materials and methods A total of 435 individuals were enrolled (195 CVD patients and 240 controls) for the case–control study. Genotyping of MTHFR C677T and MTR A2756G gene polymorphism was done by PCR-RFLP technique. Biochemical parameters were estimated by biochemical analyser. Results Metabolic variables such as serum LDL-C, TC and TG were significantly higher in patients (p < 0.0001), whereas serum HDL-C was higher in controls. Majority of the patients were having history of hypertension (57.44%; p < 0.0001) as a concomitant condition. The evaluation of genetic association showed that, MTHFR C6877T (OR: 8.89, 95% CI: 2.01–39.40) and MTR A2756G (OR: 1.48, 95% CI: 1.09–2.00) polymorphisms associated with higher risk of CVD. Conclusion The present study reveals significant differences in nongenetic variables among patients and control as well as association of gene polymorphisms with CVD risk.
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Affiliation(s)
- Jyotdeep K Raina
- Human Genetics Research cum Counselling Centre, University of Jammu, 180006, India
| | - Minakashee Sharma
- Human Genetics Research cum Counselling Centre, University of Jammu, 180006, India
| | - Rakesh K Panjaliya
- Human Genetics Research cum Counselling Centre, University of Jammu, 180006, India
| | | | - Ravi Sharma
- Human Genetics Research cum Counselling Centre, University of Jammu, 180006, India; Department of Zoology, University of Jammu, India
| | - Ashok Bakaya
- Department of Cardiology, Acharaya Shri Chander College of Medical Sciences and Hospital (ASCOMS), Sidhra, Jammu, India
| | - Parvinder Kumar
- Principal Investigator, Human Genetics Research cum Counselling Centre, University of Jammu, 180006, India; Assistant Professor, Department of Zoology, University of Jammu, India.
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Santilli F, Davì G, Patrono C. Homocysteine, methylenetetrahydrofolate reductase, folate status and atherothrombosis: A mechanistic and clinical perspective. Vascul Pharmacol 2016; 78:1-9. [DOI: 10.1016/j.vph.2015.06.009] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Revised: 06/17/2015] [Accepted: 06/20/2015] [Indexed: 10/23/2022]
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Li J, Jiang S, Zhang Y, Tang G, Wang Y, Mao G, Li Z, Xu X, Wang B, Huo Y. H-type hypertension and risk of stroke in chinese adults: A prospective, nested case-control study. J Transl Int Med 2015; 3:171-178. [PMID: 27847909 PMCID: PMC4936453 DOI: 10.1515/jtim-2015-0027] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Objectives To investigate the independent and joint associations of hyperhomocysteinemia and hypertension with incident stroke and stroke death in Chinese adults. Methods About 39,165 rural Chinese adults aged 35 years or older who had no history of stroke at the baseline study were prospectively followed to determine major cardiovascular events, with an average follow-up of 6.2 years. Using a nested case–control design, this report includes 179 incident stroke cases (121 stroke deaths) and 179 controls without vascular events from the original cohort matched by age, sex, community, and length of plasma storage. Baseline plasma total homocysteine (tHcy) measurements were obtained for all subjects. Logistic regression analysis was performed to investigate the independent and joint associations between H-type hypertension, defined as subjects with concomitant hypertension and elevated homocysteine (≥10 μmol/L), and risk of incident stroke and stroke death, after adjusting for important covariates. Results We analyzed each risk factor independently and jointly. For analysis, homocysteine was divided into three groups: low (tHcy <10 μmol/L), moderate (≥10 μmol/L tHcy <20 μmol/L), and high (tHcy≥20μmol/L). Compared to subjects in the low group, the odds ratios (95% CI) of incident stroke for those in the moderate group and the high group were 1.7 (0.8–3.7) and 3.1 (1.2–8.6), respectively. The odds ratios (95% CI) of stroke death for the moderate and high groups were 2.8 (1.1–7.4) and 5.1 (1.6–16.4), respectively. Hypertension was also independently associated with a higher risk of incident stroke and stroke death: 3.8 (2.3–6.4) and 3.2 (1.8–6.0), respectively, compared to those without hypertension. When analyzed jointly, the highest risk was found among patients with H-type hypertensive with both hyperhomocysteinemia and hypertension: 12.7 (2.8–58.0) for incident stroke and 11.7 (2.5–54.7) for stroke death. Conclusions This study provides strong evidence that hyperhomocysteinemia and hypertension are two independent, modifiable risk factors, which act additively to increase the risk of incident stroke and stroke death. The results strongly suggest that H-type hypertension is a major risk factor for vascular disease and mortality, and those with H-type hypertension may particularly benefit from homocysteine-lowering therapy along with anti-hypertension therapy in Chinese populations.
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Affiliation(s)
- Jianping Li
- Department of Cardiology, Peking University First Hospital, Beijing, China
| | - Shanqun Jiang
- School of Life Sciences, Anhui University, Hefei, China; Institute of Biomedicine, Anhui Medical University, Hefei, China
| | - Yan Zhang
- Department of Cardiology, Peking University First Hospital, Beijing, China
| | - Genfu Tang
- Institute of Biomedicine, Anhui Medical University, Hefei, China
| | - Yu Wang
- Institute of Biomedicine, Anhui Medical University, Hefei, China
| | - Guangyun Mao
- Institute of Biomedicine, Anhui Medical University, Hefei, China
| | - Zhiping Li
- Institute of Biomedicine, Anhui Medical University, Hefei, China
| | - Xiping Xu
- Institute of Biomedicine, Anhui Medical University, Hefei, China; National Clinical Research Study Center for Kidney Disease; State Key Laboratory for Organ Failure Research; Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Binyan Wang
- National Clinical Research Study Center for Kidney Disease; State Key Laboratory for Organ Failure Research; Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yong Huo
- Department of Cardiology, Peking University First Hospital, Beijing, China
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The C677T MTHFR genotypes influence the efficacy of B9 and B12 vitamins supplementation to lowering plasma total homocysteine in hemodialysis. J Nephrol 2015; 29:691-8. [DOI: 10.1007/s40620-015-0235-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 09/14/2015] [Indexed: 10/22/2022]
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Sarecka-Hujar B, Zak I, Krauze J. The TT Genotype of the MTHFR 677C>T Polymorphism Increases Susceptibility to Premature Coronary Artery Disease in Interaction with Some of the Traditional Risk Factors. ACTA MEDICA (HRADEC KRÁLOVÉ) 2015; 55:172-9. [DOI: 10.14712/18059694.2015.42] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Background: The presence of several risk factors (genetic and non-genetic) has greater impact on the risk of premature coronary artery disease (CAD) than single risk factor. Objective: The aim of the study was to establish possible relations between genotypes and alleles of 677C>T polymorphism ofMTHFRgene and some traditional risk factors e.g. elevated levels of lipid parameters and smoking in development of premature CAD. Methods: The groups comprised 152 patients with angiographically documented premature CAD (aged 42.9 ± 5.5) and 121 age-matched blood donors (aged 42.3 ± 6.5) were studied. TheMTHFR677C>T polymorphism was genotyped with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Results: Patients with TT genotype who simultaneously smoked had increased risk of premature CAD compared to non-smoking cases with CC genotype (OR = 24.62). We also found that individuals with TT genotype and elevated LDL-cholesterol (LDL-chol.) level had significantly higher risk of CAD (OR = 9.92) than individuals with normal LDL-chol. level and CC genotype. Conclusions: The present study shows that simultaneous presence ofMTHFRTT genotype and smoking or elevated levels of LDL-chol. influences the risk of premature CAD. This findings give interesting contribution to gene-environment interaction problem that may have clinical implications in the future.
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Burda P, Schäfer A, Suormala T, Rummel T, Bürer C, Heuberger D, Frapolli M, Giunta C, Sokolová J, Vlášková H, Kožich V, Koch HG, Fowler B, Froese DS, Baumgartner MR. Insights into Severe 5,10-Methylenetetrahydrofolate Reductase Deficiency: Molecular Genetic and Enzymatic Characterization of 76 Patients. Hum Mutat 2015; 36:611-21. [DOI: 10.1002/humu.22779] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 02/20/2015] [Indexed: 11/10/2022]
Affiliation(s)
- Patricie Burda
- Division of Metabolism and Children's Research Center; University Children's Hospital; Zurich CH-8032 Switzerland
| | - Alexandra Schäfer
- Division of Metabolism and Children's Research Center; University Children's Hospital; Zurich CH-8032 Switzerland
| | - Terttu Suormala
- Division of Metabolism and Children's Research Center; University Children's Hospital; Zurich CH-8032 Switzerland
| | - Till Rummel
- Department of Pediatrics; University Hospital; Münster D-48149 Germany
| | - Céline Bürer
- Division of Metabolism and Children's Research Center; University Children's Hospital; Zurich CH-8032 Switzerland
| | - Dorothea Heuberger
- Division of Metabolism and Children's Research Center; University Children's Hospital; Zurich CH-8032 Switzerland
| | - Michele Frapolli
- Division of Metabolism and Children's Research Center; University Children's Hospital; Zurich CH-8032 Switzerland
| | - Cecilia Giunta
- Division of Metabolism and Children's Research Center; University Children's Hospital; Zurich CH-8032 Switzerland
| | - Jitka Sokolová
- Institute of Inherited Metabolic Disorders; First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague; Prague Czech Republic
| | - Hana Vlášková
- Institute of Inherited Metabolic Disorders; First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague; Prague Czech Republic
| | - Viktor Kožich
- Institute of Inherited Metabolic Disorders; First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague; Prague Czech Republic
| | - Hans Georg Koch
- Department of Pediatrics; University Hospital; Münster D-48149 Germany
- Klinikum für Kinder- und Jugendmedizin; Klinikum Braunschweig; Braunschweig D-38118 Germany
| | - Brian Fowler
- Division of Metabolism and Children's Research Center; University Children's Hospital; Zurich CH-8032 Switzerland
| | - D. Sean Froese
- Division of Metabolism and Children's Research Center; University Children's Hospital; Zurich CH-8032 Switzerland
- radiz - Rare Disease Initiative Zurich; Clinical Research Priority Program for Rare Diseases, University of Zurich; Switzerland
| | - Matthias R. Baumgartner
- Division of Metabolism and Children's Research Center; University Children's Hospital; Zurich CH-8032 Switzerland
- radiz - Rare Disease Initiative Zurich; Clinical Research Priority Program for Rare Diseases, University of Zurich; Switzerland
- Zurich Center for Integrative Human Physiology; University of Zurich; Switzerland
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Shorter KR, Felder MR, Vrana PB. Consequences of dietary methyl donor supplements: Is more always better? PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2015; 118:14-20. [PMID: 25841986 DOI: 10.1016/j.pbiomolbio.2015.03.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 03/11/2015] [Accepted: 03/13/2015] [Indexed: 11/16/2022]
Abstract
Epigenetic mechanisms are now recognized to play roles in disease etiology. Several diseases increasing in frequency are associated with altered DNA methylation. DNA methylation is accomplished through metabolism of methyl donors such as folate, vitamin B12, methionine, betaine (trimethylglycine), and choline. Increased intake of these compounds correlates with decreased neural tube defects, although this mechanism is not well understood. Consumption of these methyl donor pathway components has increased in recent years due to fortification of grains and high supplemental levels of these compounds (e.g. vitamins, energy drinks). Additionally, people with mutations in one of the enzymes that assists in the methyl donor pathway (5-MTHFR) are directed to consume higher amounts of methyl donors to compensate. Recent evidence suggests that high levels of methyl donor intake may also have detrimental effects. Individualized medicine may be necessary to determine the appropriate amounts of methyl donors to be consumed, particularly in women of child bearing age.
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Affiliation(s)
- Kimberly R Shorter
- University of Florida School of Medicine, Department of Psychiatry at the McKnight Brain Institute, 1149 Newell Drive, Gainesville, FL 32611, USA
| | - Michael R Felder
- University of South Carolina, Department of Biological Sciences, 715 Sumter Street, Columbia, SC 29208, USA; Peromyscus Genetic Stock Center, University of South Carolina, 715 Sumter Street, Columbia, SC 29208, USA
| | - Paul B Vrana
- University of South Carolina, Department of Biological Sciences, 715 Sumter Street, Columbia, SC 29208, USA; Peromyscus Genetic Stock Center, University of South Carolina, 715 Sumter Street, Columbia, SC 29208, USA.
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Barnabé A, Aléssio ACM, Bittar LF, de Moraes Mazetto B, Bicudo AM, de Paula EV, Höehr NF, Annichino-Bizzacchi JM. Folate, vitamin B12 and Homocysteine status in the post-folic acid fortification era in different subgroups of the Brazilian population attended to at a public health care center. Nutr J 2015; 14:19. [PMID: 25886278 PMCID: PMC4354994 DOI: 10.1186/s12937-015-0006-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 02/09/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Folate and vitamin B12 are essential nutrients, whose deficiencies are considerable public health problems worldwide, affecting all age groups. Low levels of these vitamins have been associated with high concentrations of homocysteine (Hcy) and can lead to health complications. Several genetic polymorphisms affect the metabolism of these vitamins. The aims of this study were to assess folate, vitamin B12 and homocysteine status in distinct Brazilian individuals after the initiation of folic acid fortification by Brazilian authorities and to investigate the effects of RFC1 A80G, GCPII C1561T and MTHFR C677T polymorphisms on folate, vitamin B12 and Hcy levels in these populations. METHODS A total of 719 individuals including the elderly, children, as well as pregnant and lactating women were recruited from our health care center. Folate, vitamin B12 and Hcy levels were measured by conventional methods. Genotype analyses of RFC1 A80G, GCPII C1561T and MTHFR C677T polymorphisms were performed by PCR-RFLP. RESULTS The overall prevalence of folate and vitamin B12 deficiencies were 0.3% and 4.9%, respectively. Folate deficiency was observed only in the elderly (0.4%) and pregnant women (0.3%), whereas vitamin B12 deficiency was observed mainly in pregnant women (7.9%) and the elderly (4.2%). Plasma Hcy concentrations were significantly higher in the elderly (33.6%). Pregnant women carrying the MTHFR 677TT genotype showed lower serum folate levels (p = 0.042) and higher Hcy levels (p = 0.003). RFC1 A80G and GCPII C1561T polymorphisms did not affect folate and Hcy levels in the study group. After a multivariate analysis, Hcy levels were predicted by variables such as folate, vitamin B12, gender, age and RFC1 A80G polymorphism, according to the groups studied. CONCLUSION Our results suggest that folate deficiency is practically nonexistent in the post-folic acid fortification era in the subgroups evaluated. However, screening for vitamin B12 deficiency may be particularly relevant in our population, especially in the elderly.
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Affiliation(s)
- Aline Barnabé
- Department of Clinical Pathology, Faculty of Medical Sciences, University of Campinas, Rua Alexander Fleming, 105, Campinas, SP, 13083-881, Brazil.
| | - Ana Cláudia Morandi Aléssio
- Hematology and Hemotherapy Center, University of Campinas, Rua Carlos Chagas, 480, Campinas, SP, 13083-878, Brazil.
| | - Luis Fernando Bittar
- Hematology and Hemotherapy Center, University of Campinas, Rua Carlos Chagas, 480, Campinas, SP, 13083-878, Brazil.
| | - Bruna de Moraes Mazetto
- Hematology and Hemotherapy Center, University of Campinas, Rua Carlos Chagas, 480, Campinas, SP, 13083-878, Brazil.
| | - Angélica M Bicudo
- Department of Pediatrics, Faculty of Medical Sciences, University of Campinas, Rua Tessália Vieira de Camargo, 126, Campinas, SP, 13083-887, Brazil.
| | - Erich V de Paula
- Department of Clinical Pathology, Faculty of Medical Sciences, University of Campinas, Rua Alexander Fleming, 105, Campinas, SP, 13083-881, Brazil.
| | - Nelci Fenalti Höehr
- Department of Clinical Pathology, Faculty of Medical Sciences, University of Campinas, Rua Alexander Fleming, 105, Campinas, SP, 13083-881, Brazil.
| | - Joyce M Annichino-Bizzacchi
- Hematology and Hemotherapy Center, University of Campinas, Rua Carlos Chagas, 480, Campinas, SP, 13083-878, Brazil.
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Bellia C, Bivona G, Caruso A, Elce A, Amato F, Spataro R, Colletti T, Pivetti A, Russo V, Scazzone C, Lo Sasso B, Castaldo G, La Bella V, Ciaccio M. MTHFR C677T allelic variant is not associated with plasma and cerebrospinal fluid homocysteine in amyotrophic lateral sclerosis. Clin Chem Lab Med 2015; 53:e73-e75. [PMID: 25229416 DOI: 10.1515/cclm-2014-0465] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 07/28/2014] [Indexed: 02/06/2025]
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