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Fan Q, Meng Y, Nie Z, Yi Z, Chen L, Xie S. The role of inflammatory factors in mediating the causal effects of type 1 diabetes mellitus on idiopathic pulmonary fibrosis: A two-step Mendelian randomization study. Medicine (Baltimore) 2025; 104:e41320. [PMID: 39854757 PMCID: PMC11771656 DOI: 10.1097/md.0000000000041320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 12/15/2024] [Accepted: 01/03/2025] [Indexed: 01/26/2025] Open
Abstract
While recent studies suggested a potential causal link between type 1 diabetes mellitus (T1DM) but not type 2 diabetes mellitus (T2DM) and idiopathic pulmonary fibrosis (IPF), the involved mechanism remains unclear. Here, using a Mendelian randomization (MR) approach, we verified the causal relationship between the two types of diabetes mellitus and IPF and investigated the possible role of inflammation in the association between diabetes mellitus and IPF. Based on genome-wide association study (GWAS) summary data of T1DM, T2DM, and IPF, the univariable MR, multivariable MR (MVMR), and mediation MR were successively used to analyze the causal relationship. Inverse variance weighted was used as the main method to infer the causal effect, together with a series of sensitivity analyses. The univariable MR showed that only T1DM increased the risk of IPF, and there was no significant causal relationship between T2DM and IPF. The MVMR further verified that there was an independent direct causal effect of T1DM on IPF. Further mediation analysis showed that this effect was partly mediated by increasing C-X-C motif chemokine ligand 10 (CXCL10) and interleukin-12 subunit beta (IL-12B). In conclusion, T1DM is related to an increased risk of IPF. Notably, the causal effect was partially mediated by CXCL10 and IL-12B. Hence, monitoring T1DM patients may help in the early detection and prevention of IPF.
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Affiliation(s)
- Qinglu Fan
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yang Meng
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhihao Nie
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zuohuizi Yi
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Liao Chen
- Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Wuhan, China
| | - Songping Xie
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
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Duan Y, Wang X, Li M, Zhang C, Li S, Wang R, Zhao J. Association of interleukin-12B gene polymorphisms and mRNA expression with preeclampsia. Eur J Obstet Gynecol Reprod Biol 2021; 269:77-82. [PMID: 34971914 DOI: 10.1016/j.ejogrb.2021.12.016] [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: 09/09/2021] [Revised: 11/17/2021] [Accepted: 12/11/2021] [Indexed: 11/04/2022]
Abstract
OBJECTIVE To explore the effects of functional genetic polymorphisms of the interleukin-12B (IL-12B) gene on the susceptibility to preeclampsia in northern Chinese women. STUDY DESIGN Maternal peripheral blood from 306 preeclamptic women and 310 control women and the placentas from 52 preeclamptic and 55 control women were collected. Two polymorphisms (rs17860508 and rs3212227) of the IL-12B gene were genotyped by polymerase chain reaction (PCR) with a direct sequencing method. The mRNA expression of IL-12B in the placentas was measured by quantitative real-time PCR (qRT-PCR). RESULTS Significant differences were observed between preeclamptic women and the control group in the genotype frequencies of rs17860508 (P = 0.017). Compared with the TTAGAG/TTAGAG genotype of rs17860508, the GC/GC genotype were associated with a higher risk of preeclampsia (adjusted OR: 1.95; 95% CI = 1.18-3.22; P = 0.009), especially the early-onset preeclampsia (adjusted OR: 2.40; 95% CI = 1.23-4.68; P = 0.010). The qRT-PCR results showed that the mRNA levels of IL-12B were significantly higher in the placentas of preeclampsia patients than that in the placentas of controls (P = 0.001). Moreover, the expression of IL-12B mRNA was significantly higher in the placentas of patients carrying the GC/GC genotype than in those carrying the TTAGAG/GC (P = 0.007) and TTAGAG/TTAGAG (P = 0.005) genotypes. CONCLUSION The GC/GC genotype of rs17860508 polymorphism may be a risk factor for the early-onset preeclampsia by upregulating the expression of IL-12B in northern Chinese women.
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Affiliation(s)
- Ya Duan
- Department of Obstetrics, Hebei General Hospital, Shijiazhuang, Hebei 050011, PR China
| | - Xinling Wang
- Department of Obstetrics, Hebei General Hospital, Shijiazhuang, Hebei 050011, PR China
| | - Min Li
- Department of Obstetrics, Hebei General Hospital, Shijiazhuang, Hebei 050011, PR China
| | - Cui Zhang
- Department of Obstetrics, Hebei General Hospital, Shijiazhuang, Hebei 050011, PR China
| | - Sisi Li
- Department of Obstetrics, Hebei General Hospital, Shijiazhuang, Hebei 050011, PR China
| | - Runfang Wang
- Department of Obstetrics, Hebei General Hospital, Shijiazhuang, Hebei 050011, PR China
| | - Jian Zhao
- Department of Gynecology and Obstetrics, the People Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei 050011, PR China.
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Ben Selma W, Laribi AB, Alibi S, Saad A, Boukadida J. Interaction analysis of IL-12A and IL-12B gene variants with chronic hepatitis B infection in Tunisian patients. Immunol Lett 2020; 225:50-56. [PMID: 32554051 DOI: 10.1016/j.imlet.2020.06.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 05/09/2020] [Accepted: 06/08/2020] [Indexed: 12/12/2022]
Abstract
Given the key role of interleukin-12 (IL-12) in the control of HBV, we investigated the possible correlation between IL-12A rs568408 and IL-12B rs3212227 polymorphisms and the risk of chronic HBV infection in Tunisian population. Two hundred patients with chronic HBV infection and two hundred healthy controls were genotyped using PCR-RFLP. A allele, AA and AG genotypes of IL-12A rs568408 were more represented in the chronic HBV infection group compared to the control group, and they were associated with 1.65-, 2.58- and 3.13-fold risks of developing this infection, respectively. Gene-gene interaction analysis showed that subjects carrying the IL-12A rs568408AA/AG and IL-12B rs3212227AA genotypes had a 3.16-fold increased risk of chronic HBV infection. This study suggested that IL-12A rs568408 and gene-gene interactions of IL-12A rs568408 and IL-12B rs3212227 contributed to the outcome of chronic HBV infection, meanwhile indicating their usefulness as a predictive and diagnostic biomarker of chronic HBV infection.
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Affiliation(s)
- Walid Ben Selma
- Laboratory of Microbiology, Genetic Characterization of Infectious Diseases, UR12SP34 University Hospital Farhat Hached, Sousse, Tunisia; Laboratory of Studying Biological and Genetic Markers for Early Diagnosis and Follow-Up of Neurological Diseases, LR18ES47, Faculty of Medicine, Sousse, Tunisia; High Institute of Applied Sciences and Technology, Mahdia, Tunisia.
| | - Ahmed Baligh Laribi
- Laboratory of Microbiology, Genetic Characterization of Infectious Diseases, UR12SP34 University Hospital Farhat Hached, Sousse, Tunisia
| | - Sana Alibi
- Laboratory of Microbiology, Genetic Characterization of Infectious Diseases, UR12SP34 University Hospital Farhat Hached, Sousse, Tunisia
| | - Afef Saad
- Department of Microbiology, Faculty of Medicine, Sousse, Tunisia
| | - Jalel Boukadida
- Laboratory of Microbiology, Genetic Characterization of Infectious Diseases, UR12SP34 University Hospital Farhat Hached, Sousse, Tunisia; Department of Microbiology, Faculty of Medicine, Sousse, Tunisia
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A Functional Polymorphism in the Promoter Region of Interleukin-12B Increases the Risk of Colorectal Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2091781. [PMID: 32149085 PMCID: PMC7054766 DOI: 10.1155/2020/2091781] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 01/31/2020] [Indexed: 01/05/2023]
Abstract
Objective To investigate whether the polymorphisms of interleukin-12B (IL-12B) were associated with the risk of developing colorectal cancer (CRC). Patients and Methods. Genotypes of rs17860508 and rs3212227 were determined by polymerase chain reaction with a direct sequencing method in 329 CRC patients and 342 matched healthy control subjects. The expression of IL-12B) were associated with the risk of developing colorectal cancer (CRC). Results Compared with TTAGAG/TTAGAG genotype of rs17860508, the GC/GC and TTAGAG/GC genotypes may significantly increase the risk of CRC (OR = 1.81, 95% CI = 1.18-2.78; OR = 1.46, 95% CI = 1.01-2.12, respectively). Furthermore, the mRNA levels of IL-12B) were associated with the risk of developing colorectal cancer (CRC). P=0.009) and TTAGAG/TTAGAG (P=0.009) and TTAGAG/TTAGAG (. Conclusion These data suggested that the rs17860508 GC/GC genotype might upregulate IL-12B expression at the transcriptional level and thus increase the risk of CRC.IL-12B) were associated with the risk of developing colorectal cancer (CRC).
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Shen TC, Tsai CW, Chang WS, Wang S, Chao CY, Hsiao CL, Chen WC, Hsia TC, Bau DT. Association of Interleukin-12A rs568408 with Susceptibility to Asthma in Taiwan. Sci Rep 2017; 7:3199. [PMID: 28600552 PMCID: PMC5466618 DOI: 10.1038/s41598-017-03523-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 05/02/2017] [Indexed: 11/22/2022] Open
Abstract
Asthma is an inflammatory disease and interleukin 12 (IL-12) may play a regulatory role in allergen-induced inflammation. The aim of this study was to investigate the association of polymorphisms in IL-12A/IL-12B with asthma. The asthma group included 198 adult patients and the control group included 453 individuals without asthma that were frequency-matched by gender and age. The distribution of genotypic and allelic frequencies of IL-12A rs568408 demonstrated significant differences between case and control groups. Specifically, the percentages of AA genotype of IL-12A rs568408 was significantly higher among asthmatic patients in Taiwan than healthy controls, compared to GG genotype. No significant difference was observed among the IL-12A rs2243115 and IL-12B rs3212227 genotypes between case and control groups. In addition, the A allele at IL-12A rs568408 was associated with more severe symptoms (P = 0.0085) among asthmatic patients. These results suggest that IL-12A rs568408 may contribute to the etiology and symptoms severity of asthma, indicating its usefulness as a predictive and diagnostic biomarker of asthma.
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Affiliation(s)
- Te-Chun Shen
- Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan, ROC.,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, ROC.,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, ROC
| | - Chia-Wen Tsai
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, ROC
| | - Wen-Shin Chang
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, ROC
| | - Shengyu Wang
- Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Xi'an Medical University, Xi'an, P.R. China
| | - Che-Yi Chao
- Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, ROC
| | - Chieh-Lun Hsiao
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, ROC
| | - Wei-Chun Chen
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, ROC.,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, ROC.,Department of Respiratory Therapy, China Medical University, Taichung, Taiwan, ROC
| | - Te-Chun Hsia
- Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, ROC. .,Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, ROC. .,Department of Respiratory Therapy, China Medical University, Taichung, Taiwan, ROC.
| | - Da-Tian Bau
- Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan, ROC. .,Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, ROC. .,Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan, ROC.
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Sam SS, Teoh BT, Chinna K, AbuBakar S. High producing tumor necrosis factor alpha gene alleles in protection against severe manifestations of dengue. Int J Med Sci 2015; 12:177-86. [PMID: 25589894 PMCID: PMC4293183 DOI: 10.7150/ijms.8988] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Accepted: 12/09/2014] [Indexed: 11/13/2022] Open
Abstract
UNLABELLED Dengue virus (DENV) infection usually presents with mild self-limiting dengue fever (DF). Few however, would present with the more severe form of the disease, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). In the present study, the association between IL-12B, IL-10 and TNF-α gene polymorphisms and dengue severity was investigated. METHODS A case-control study was performed on a total of 120 unrelated controls, 86 DF patients and 196 DHF/DSS patients. The polymorphisms in IL-12B, IL-10 and TNF-α genes were genotyped using PCR-RFLP and PCR-sequencing methods. RESULTS A protective association of TNF-α -308A allele and -308GA genotype against DHF/DSS was observed, while TNF-α -238A allele and -238GA genotype were associated with DHF/DSS. A combination of TNF-α -308GA+AA genotype and IL-10 non-GCC haplotypes, IL-12B pro homozygotes (pro1/pro1, pro2/pro2) and IL-12B 3'UTR AC were significantly correlated with protective effects against DHF/DSS. An association between the cytokine gene polymorphisms and protection against the clinical features of severe dengue including thrombocytopenia and increased liver enzymes was observed in this study. CONCLUSION The overall findings of the study support the correlation of high-producer TNF-α genotypes combined with low-producer IL-10 haplotypes and IL-12B genotypes in reduced risk of DHF/DSS.
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Affiliation(s)
- Sing-Sin Sam
- 1. Tropical Infectious Diseases Research and Education Center (TIDREC), Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Boon-Teong Teoh
- 1. Tropical Infectious Diseases Research and Education Center (TIDREC), Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Karuthan Chinna
- 2. Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Sazaly AbuBakar
- 1. Tropical Infectious Diseases Research and Education Center (TIDREC), Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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Grzegorzewska AE, Ostromecki G, Zielińska P, Mostowska A, Jagodziński PP. T-cell cytokine gene polymorphisms and vitamin D pathway gene polymorphisms in end-stage renal disease due to type 2 diabetes mellitus nephropathy: comparisons with health status and other main causes of end-stage renal disease. J Diabetes Res 2014; 2014:120317. [PMID: 25587543 PMCID: PMC4284966 DOI: 10.1155/2014/120317] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 09/22/2014] [Accepted: 09/22/2014] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND T-cell cytokine gene polymorphisms and vitamin D pathway gene polymorphisms were evaluated as possibly associated with end-stage renal disease (ESRD) resulting from type 2 diabetes mellitus (DM) nephropathy. METHODS Studies were conducted among hemodialysis (HD) patients with ESRD due to type 2 DM nephropathy, chronic glomerulonephritis, chronic infective tubulointerstitial nephritis, and hypertensive nephropathy as well as in healthy subjects. A frequency distribution of T-cell-related interleukin (IL) genes (IL18 rs360719, IL12A rs568408, IL12B rs3212227, IL4R rs1805015, IL13 rs20541, IL28B rs8099917, IL28B, and rs12979860) and vitamin D pathway genes (GC genes: rs2298849, rs7041, and rs1155563; VDR genes: rs2228570, rs1544410; and RXRA genes: rs10776909, rs10881578, and rs749759) was compared between groups. RESULTS No significant differences in a frequency distribution of tested polymorphisms were shown between type 2 DM nephropathy patients and controls. A difference was found in IL18 rs360719 polymorphic distribution between the former group and chronic infective tubulointerstitial nephritic patients (P trend = 0.033), which also differed in this polymorphism from controls (P trend = 0.005). CONCLUSION T-cell cytokine and vitamin D pathway gene polymorphisms are not associated with ESRD due to type 2 DM nephropathy in Polish HD patients. IL18 rs360719 is probably associated with the pathogenesis of chronic infective tubulointerstitial nephritis.
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Affiliation(s)
- Alicja E. Grzegorzewska
- Department of Nephrology, Transplantology and Internal Diseases, Poznań University of Medical Sciences (PUMS), 49 Przybyszewskiego Boulevard, 60-355 Poznań, Poland
| | - Grzegorz Ostromecki
- DaVita Clinic Piła Dialysis Center, Wojska Polskiego 43, 64-420 Piła, Poland
| | - Paulina Zielińska
- Student Nephrology Research Group, Department of Nephrology, Transplantology and Internal Diseases, PUMS, Przybyszewskiego 49, 60-355 Poznań, Poland
| | - Adrianna Mostowska
- Department of Biochemistry and Molecular Biology, PUMS, Święcickiego 6, 60-781 Poznań, Poland
| | - Paweł P. Jagodziński
- Department of Biochemistry and Molecular Biology, PUMS, Święcickiego 6, 60-781 Poznań, Poland
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The effects of socioeconomic status, clinical factors, and genetic ancestry on pulmonary tuberculosis disease in northeastern Mexico. PLoS One 2014; 9:e94303. [PMID: 24728409 PMCID: PMC3984129 DOI: 10.1371/journal.pone.0094303] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 03/14/2014] [Indexed: 12/15/2022] Open
Abstract
Diverse socioeconomic and clinical factors influence susceptibility to tuberculosis (TB) disease in Mexico. The role of genetic factors, particularly those that differ between the parental groups that admixed in Mexico, is unclear. The objectives of this study are to identify the socioeconomic and clinical predictors of the transition from latent TB infection (LTBI) to pulmonary TB disease in an urban population in northeastern Mexico, and to examine whether genetic ancestry plays an independent role in this transition. We recruited 97 pulmonary TB disease patients and 97 LTBI individuals from a public hospital in Monterrey, Nuevo León. Socioeconomic and clinical variables were collected from interviews and medical records, and genetic ancestry was estimated for a subset of 142 study participants from 291,917 single nucleotide polymorphisms (SNPs). We examined crude associations between the variables and TB disease status. Significant predictors from crude association tests were analyzed using multivariable logistic regression. We also compared genetic ancestry between LTBI individuals and TB disease patients at 1,314 SNPs in 273 genes from the TB biosystem in the NCBI BioSystems database. In crude association tests, 12 socioeconomic and clinical variables were associated with TB disease. Multivariable logistic regression analyses indicated that marital status, diabetes, and smoking were independently associated with TB status. Genetic ancestry was not associated with TB disease in either crude or multivariable analyses. Separate analyses showed that LTBI individuals recruited from hospital staff had significantly higher European genetic ancestry than LTBI individuals recruited from the clinics and waiting rooms. Genetic ancestry differed between individuals with LTBI and TB disease at SNPs located in two genes in the TB biosystem. These results indicate that Monterrey may be structured with respect to genetic ancestry, and that genetic differences in TB susceptibility in parental populations may contribute to variation in disease susceptibility in the region.
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Cytokine Polymorphisms, Their Influence and Levels in Brazilian Patients with Pulmonary Tuberculosis during Antituberculosis Treatment. Tuberc Res Treat 2013; 2013:285094. [PMID: 23634300 PMCID: PMC3619634 DOI: 10.1155/2013/285094] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 02/19/2013] [Accepted: 02/26/2013] [Indexed: 12/04/2022] Open
Abstract
Cytokines play an essential role during active tuberculosis disease and cytokine genes have been described in association with altered cytokine levels. Therefore, the aim of this study was to verify if IFNG, IL12B, TNF, IL17A, IL10, and TGFB1 gene polymorphisms influence the immune response of Brazilian patients with pulmonary tuberculosis (PTB) at different time points of antituberculosis treatment (T1, T2, and T3). Our results showed the following associations: IFNG +874 T allele and IFNG +2109 A allele with higher IFN-γ levels; IL12B +1188 C allele with higher IL-12 levels; TNF −308 A allele with higher TNF-α plasma levels in controls and mRNA levels in PTB patients at T1; IL17A A allele at rs7747909 with higher IL-17 levels; IL10 −819 T allele with higher IL-10 levels; and TGFB1 +29 CC genotype higher TGF-β plasma levels in PTB patients at T2. The present study suggests that IFNG +874T/A, IFNG +2109A/G, IL12B +1188A/C, IL10 −819C/T, and TGFB1 +21C/T are associated with differential cytokine levels in pulmonary tuberculosis patients and may play a role in the initiation and maintenance of acquired cellular immunity to tuberculosis and in the outcome of the active disease while on antituberculosis treatment.
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Sun M, Fu SM, Dong GY, Wu D, Wang GX, Wu Y. Inflammatory factors gene polymorphism in recurrent oral ulceration. J Oral Pathol Med 2013; 42:528-34. [DOI: 10.1111/jop.12048] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2013] [Indexed: 11/26/2022]
Affiliation(s)
- Mao Sun
- Center for DNA Typing; Fourth Military Medical University; Xi'an China
- Department of Biochemistry and Molecular Biology; Fourth Military Medical University; Xi'an China
| | - Shan-Min Fu
- Department of Orthodontics; Fourth Military Medical University; Xi'an China
- School of Stomatology; Fourth Military Medical University; Xi'an China
| | - Guang-Ying Dong
- Department of Periodontics and Oral Medicine; Fourth Military Medical University; Xi'an China
- School of Stomatology; Fourth Military Medical University; Xi'an China
| | - Dan Wu
- Center for DNA Typing; Fourth Military Medical University; Xi'an China
- Department of Biochemistry and Molecular Biology; Fourth Military Medical University; Xi'an China
| | - Guo-Xia Wang
- Center for DNA Typing; Fourth Military Medical University; Xi'an China
- Department of Biochemistry and Molecular Biology; Fourth Military Medical University; Xi'an China
| | - Yuanming Wu
- Center for DNA Typing; Fourth Military Medical University; Xi'an China
- Department of Biochemistry and Molecular Biology; Fourth Military Medical University; Xi'an China
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Hadžija MP, Korolija M, Jemin N, Pavković I, Pavković P, Medvidović EP, Hadžija M. Polymorphisms in the IL-18 and IL-12B genes and their association with the clinical outcome in Croatian patients with Type 1 diabetes. Gene 2012; 512:477-81. [PMID: 23137633 DOI: 10.1016/j.gene.2012.10.029] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2012] [Accepted: 10/21/2012] [Indexed: 12/12/2022]
Abstract
Genetic variants of IL-18 and IL-12B may be important in immunoregulatory abnormalities, observed in the patients with Type 1 diabetes mellitus (T1DM), that contribute to individual differences in response to a treatment. Therefore, we examined the significance of IL-18-137G/C, IL-18-607C/A, and IL-12B A/C polymorphisms in Croatians (187 patients, 236 controls), not only as factors that contribute to susceptibility to T1DM, but also as determinants of the clinical presentation of disease. The polymorphism screening has been performed using PCR sequence-specific primers (IL-18) or PCR-RFLP (IL-12B) approach. Results were evaluated by GraphPad Prism and Sigma Stat 3.5, Arlequin software and calculator for Hardy-Weinberg equilibrium. The genotype, allele and haplotype distribution were not statistically different between the patients and control subjects. The clinical parameter analysis revealed that patients with minor alleles at each locus, IL-18-137C/-607A, were significantly younger at T1DM onset than carriers of major alleles, IL-18-137G/-607C (20 vs 23.5 years). Moreover, the concomitant presence of minor alleles not only of IL-18 but also of IL-12B, is associated with the risk of disease progression even at younger age. These patients developed diabetes at 16 years of age, what is significantly earlier (p=0.044) compared to 25.5 years of age in patients with common alleles IL-18-137G/-607C/IL-12B A. Furthermore, combined genotype analysis of IL-18 and IL-12B has pointed out that patients with CC/AA/AA genotype have the worst glucose control based on HbA1c (8.7%, range 6.8-13.1%). In conclusion, susceptibility to T1DM in Croatians is not strongly associated with IL-18-137/-607 and IL-12B polymorphisms. These SNPs are associated with the higher risk of earlier disease development and might be implicated in the effectiveness of glycemic control.
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Kaarvatn MH, Vrbanec J, Kulic A, Knezevic J, Petricevic B, Balen S, Vrbanec D, Dembic Z. Single nucleotide polymorphism in the interleukin 12B gene is associated with risk for breast cancer development. Scand J Immunol 2012; 76:329-35. [PMID: 22702905 DOI: 10.1111/j.1365-3083.2012.02736.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
We analysed the association of a single nucleotide polymorphism (SNP) in the gene encoding the IL-12 subunit p40 (IL12B, rs3212227, A>C) with breast cancer. The SNPs allelic and genotypic frequencies were compared between patients (n = 191) and healthy (n = 194) women in a case-control study from Croatia. The major allele (A) was associated with susceptibility to breast cancer (P = 0.003; OR = 1.67; 95% CI: 1.17-2.38). Likewise, the minor allele (C) was significantly correlated with protection (P = 0.003; OR = 0.60; 95% CI: 0.42-0.86). At the genotype level, AA homozygosity was significantly associated with predisposition to disease (P = 0.013; OR = 1.68, 95% CI: 1.09-2.59), whereas the minor allele homozygosity (CC) was correlated with protection to disease (P = 0.020, OR = 0.28, 95% CI: 0.09-0.91). The heterozygous genotype showed no significant correlation with disease. The product of the IL12B gene (IL-12 p40) can either form a homodimeric cytokine or be part of two pro-inflammatory (IL-12 and IL-23) cytokines. It is presently unclear whether the major allele is associated with higher or lower protein levels of IL-12 p40 and IL-12 p70, which are critical in inflammation and adaptive immune responses. However, as the A allele is high producer of IL12B (p40) mRNA, these results might imply that higher levels of IL-12 p40 (either as homodimers or joined with one or both of the other two subunits) predispose to breast cancer.
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Affiliation(s)
- M H Kaarvatn
- Molecular Genetics Laboratory, Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
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Li LJ, Pan XM, Sima X, Li ZH, Zhang LS, Sun H, Zhu Y, Liang WB, Gao LB, Zhang L. Interactions of interleukin-12A and interleukin-12B polymorphisms on the risk of intracranial aneurysm. Mol Biol Rep 2012; 39:11217-23. [PMID: 23065210 DOI: 10.1007/s11033-012-2031-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Accepted: 10/02/2012] [Indexed: 11/28/2022]
Abstract
Several lines of evidence indicate that inflammatory processes play pivotal role in the development of intracranial aneurysm (IA). Recently, polymorphisms in the interleukin-12 (IL-12) gene were shown to be associated with immune-mediated inflammatory disease. The aim of this study was to investigate the interactions of IL-12A and IL-12B polymorphisms on the risk of IA in a Chinese population. A total of 422 individuals (including 164 patients with IA and 258 controls) were involved in the study. The polymorphisms (i.e., rs2243115 and rs568408 in IL-12A and rs3212227 in IL-12B) were genotyped by polymerase chain reaction-restriction fragment length polymorphism assay and DNA sequencing. We found an association of the AC/CC genotypes and C allele of IL-12B rs3212227 with an increased risk of IA, compared with the AA genotype and A allele (AC/CC vs. AA: OR = 2.09, 95 % CI: 1.29-3.38; C vs. A: OR = 1.45, 95 % CI: 1.10-1.91). Moreover, a significant gene interaction of IL-12A and IL-12B was evident on the risk of IA, and subjects carrying variant genotypes of IL-12B rs3212227 had an increased risk of IA. In the stratified analysis by gender, the IL-12B rs3212227 AC/CC genotypes had an increased risk of IA compared with the AA genotype in male patients (AC/CC vs. AA: OR = 4.63, 95 % CI: 1.92-11.16). These findings suggest that the IL-12A and IL-12B independently and jointly be involved in the susceptibility to IA.
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Affiliation(s)
- Li-Juan Li
- Department of Forensic Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China
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14
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Grzegorzewska AE, Wobszal PM, Mostowska A, Jagodziński PP. Antibodies to hepatitis B virus surface antigen and interleukin 12 and interleukin 18 gene polymorphisms in hemodialysis patients. BMC Nephrol 2012; 13:75. [PMID: 22863216 PMCID: PMC3468411 DOI: 10.1186/1471-2369-13-75] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Accepted: 07/28/2012] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The interleukin (IL)18 rs360719 CC genotype is associated with the development of antibodies to hepatitis B virus surface antigen (anti-HBs) in hemodialysis (HD) patients. IL18 shares biological properties with IL12 in promoting the T-hepler 1 (Th1) system. We studied whether polymorphisms in the IL12A 3` untranslated region (UTR) and IL12B 3`UTR may contribute to anti-HBs development (titre ≥ 10 IU/L) in HD patients either individually or jointly with the IL18 polymorphism. METHODS In 518 HD patients and 240 controls the IL12A rs568408 3'UTR G > A polymorphism was genotyped by high-resolution melting curve analysis. Polymerase chain reaction restriction fragment length polymorphism was used to detect the IL12B rs3212227 3'UTR A > C and IL18 -1297 T > C rs360719 polymorphisms. The associations between the IL12A, IL12B and IL18 genotypes and the risk of impaired anti-HBs development were estimated by computing the odds ratios and their 95% confidence intervals using logistic regression analysis. RESULTS In the logistic regression analysis, the higher frequency of rs360719 CC individually (2.9% in 207 patients without anti-HBs development vs 8.0% in 311 patients with anti-HBs development, p = 0.009) and of rs360719 CC combined with rs568408 GG (p = 0.048), rs568408 GA (p = 0.035), rs568408 GG/AA (p = 0.034) or rs3212227 AA (p = 0.046) was associated with an increased chance for the development of anti-HBs in HD patients. Patients bearing both rs568408 AA and rs360719 TT had a 10.9-fold or 8.9-fold lower chance, respectively, to develop anti-HBs compared with those carrying any other genotype (p = 0.005) or those who had both wild-type rs568408 GG and rs360719 TT (p = 0.011). Carriers of both rs3212227 CC and rs360719 TC had a 4.6-fold lower chance for anti-HBs development than carriers of any other genotype (p = 0.042). CONCLUSION Development of anti-HBs in HD patients is associated with gene polymorphisms of interleukins involved in the Th1 system.
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Affiliation(s)
- Alicja E Grzegorzewska
- Chair and Department of Nephrology, Transplantology and Internal Diseases Poznań University of Medical Sciences, 49 Przybyszewskiego Blvd, 60-355, Poznań, Poland
| | - Piotr M Wobszal
- Chair and Department of Nephrology, Transplantology and Internal Diseases Poznań University of Medical Sciences, 49 Przybyszewskiego Blvd, 60-355, Poznań, Poland
| | - Adrianna Mostowska
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, Poznań, Poland
| | - Paweł P Jagodziński
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, Poznań, Poland
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15
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van Wanrooij RLJ, Zwiers A, Kraal G, Bouma G. Genetic variations in interleukin-12 related genes in immune-mediated diseases. J Autoimmun 2012; 39:359-68. [PMID: 22819329 DOI: 10.1016/j.jaut.2012.06.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Revised: 06/13/2012] [Accepted: 06/24/2012] [Indexed: 12/20/2022]
Abstract
The interleukin-12 (IL-12) family comprises a group of heterodimeric cytokines and their respective receptors that play key roles in immune responses. A growing number of autoimmune diseases has been found to be associated with genetic variation in these genes. Based on their respective associations with the IL-12 genes, autoimmune diseases appear to cluster in two groups that either show strong associations with the Th1/Th17 pathway (as indicated by genetic association with IL12B and IL23R) or the Th1/IL-35 pathway as the consequence of their association with polymorphisms in the IL12A gene region. The genetic associations are described in relation to what is known of the functionality of these genes in the various diseases. Comparing association data for gene families in different diseases may lead to better insight in the function of the genes in the onset and course of the disease.
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Affiliation(s)
- R L J van Wanrooij
- Department of Gastroenterology and Hepatology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
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Abstract
The last decade has seen the emergence of immunomodulators as therapeutic agents in cancer treatment. Interleukins (ILs) are a category of small cell-signaling molecules that organize communication and interaction between immune cells and therefore they could be used as perfect immunomodulators. IL-12 is a promising candidate for cancer immunotherapy since it plays a major role in development of antitumor immune response. Numerous studies report that IL-12 promotes an effective destruction of cancer cells both in vivo and in vitro. In addition, IL-12 has anti-angiogenic activity and it is able to dramatically decrease tumor-supportive activities of tumor-associated macrophages. The first part of the review is devoted to immunobiology of IL-12. Signaling pathways of IL-12 as well as clinical trials of this cytokine are discussed. The second part of the review is concerned on the inherited variations in IL-12A and IL-12B genes that could modulate cancer susceptibility, and as a consequence, possess predictive, therapeutic, or prognostic significance. It is known that functional single nucleotide polymorphisms (SNPs) in IL-12A and IL-12B genes may dramatically affect on protein expression level, or alter its functions, which may lead to immune disorders, autoimmune diseases, and eventually contribute to cancer occurrence. The list of genetic polymorphisms for further investigations might include the following: IL-12B_+1188A/C (rs3212227), IL-12A_+277G/A (rs568408), IL-12A_-798T/A (rs582054), IL-12A_-504T/G (rs190533), IL-12A_-1148T/C (rs2243123), and IL-12B_+16974 A/C. Perhaps, some of these SNPs may become an attractive target for oncogenomics and possibly could be used in programs of early cancer diagnosis as well as cancer prevention in the nearest future.
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Affiliation(s)
- Arseniy E Yuzhalin
- Department of Genetics, Kemerovo State University, Kemerovo, Russian Federation.
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17
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Roszak A, Mostowska A, Sowińska A, Lianeri M, Jagodziński PP. Contribution of IL12A and IL12B Polymorphisms to the Risk of Cervical Cancer. Pathol Oncol Res 2012; 18:997-1002. [DOI: 10.1007/s12253-012-9532-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2011] [Accepted: 04/08/2012] [Indexed: 12/20/2022]
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Wang C, Zhang X, Zhu B, Hu D, Wu J, Yu R, Zhao W. Relationships between tumour necrosis factor-α, interleukin-12B and interleukin-10 gene polymorphisms and hepatitis B in Chinese Han haemodialysis patients. Nephrology (Carlton) 2012; 17:167-74. [PMID: 22070668 DOI: 10.1111/j.1440-1797.2011.01539.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
AIM To investigate the possible association of gene polymorphisms of tumour necrosis factor (TNF)-α (-238 and -308), interleukin (IL)-10 (-592 and -819) and 3' untranslated region (3'UTR) of the IL12B (-1188) and hepatitis B in Chinese Han haemodialysis (HD) patients. METHODS The genotyping of TNF-α -238 and -308, IL-10 -592 and -819 and 3'UTR of the IL12B were performed by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) method. RESULTS The TNF-α-238 A allele, the IL12B 3'UTR C/C, C/A genotypes were associated with decreased susceptibility to hepatitis B viral infection (P = 0.047, P = 0.003 and P = 0.001 respectively). The frequencies of IL-10-592 A/A genotype, IL-10-819 T/T genotype were lower in the HBV persistence group (P = 0.029 and P = 0.019) than those in the virus clearance group. CONCLUSIONS TNF-α and IL12B 3'UTR gene polymorphisms may be associated with HBV susceptibility and IL-10 gene polymorphisms may be related to the HBV persistence infection in Chinese Han HD patients.
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Affiliation(s)
- Cuiyu Wang
- Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Sima X, Xu J, Li Q, Luo L, Liu J, You C. Gene-gene interactions between interleukin-12A and interleukin-12B with the risk of brain tumor. DNA Cell Biol 2011; 31:219-23. [PMID: 22011063 DOI: 10.1089/dna.2011.1331] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Emerging evidence from preclinical and clinical studies has shown that interleukin-12 (IL-12) has some effectiveness against endogenously arising brain tumor. The aim of this study was to investigate interactions of IL-12A and IL-12B polymorphisms on the risk of brain tumor. We analyzed IL-12A rs2243115 and IL-12B rs3212227 polymorphisms in 170 patients with brain tumor and 222 healthy controls in a Chinese population using a polymerase chain reaction-restriction fragment length polymorphism assay and DNA sequencing method. Individuals carrying a G allele of IL-12A rs2243115 had a significantly higher risk of developing brain tumor compared with those carrying a T allele (odds ratio [OR]=2.01, 95% confidence interval [CI], 1.17-3.45). After stratification analysis according to tumor types, a similarly higher risk was detected in patients with glioma (OR=2.56, 95% CI, 1.25-5.21). When gene-gene interactions were examined, carriers at both loci rs2243115 TG/GG and rs3212227 AC/CC had a 2.62-fold increased risk of glioma compared with those with rs2243115 TT and rs3212227 AC/CC genotypes (OR=2.62, 95% CI, 1.05-6.50). This study provides evidence that IL-12A rs2243115 may be associated with the risk of brain tumor. Additionally, gene-gene interactions of IL-12A rs2243115 and IL-12B rs3212227 may contribute to brain tumor susceptibility.
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Affiliation(s)
- Xiutian Sima
- Department of Neurosurgery, West China Hospital of Sichuan University Chengdu, P.R. China
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20
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Abstract
AbstractIn diabetic retinopathy (DR) and other angiogenesis-associated diseases, increased levels of cytokines, inflammatory cells, and angiogenic factors are present. We investigated the hypothesis that rs2243250 polymorphism of the interleukin 4 (IL-4) gene or rs1800896 polymorphism of the interleukin 10 (IL-10) gene, and rs3212227 polymorphism of the 3’ untranslated region (3’ UTR) of the interleukin-12 p40 gene (IL12B) may be associated with the development of proliferative diabetic retinopathy (PDR) in Caucasians with type 2 diabetes (DM2). This cross sectional case — control study included 189 patients with PDR and 187 patients with type 2 diabetes without PDR. Polymorphisms rs1800896 of the IL-10 gene, rs2243250 of the IL-4 gene, and rs3212227 of IL12B gene were analyzed by ARMS -PCR and RFLP -PCR methods. Multivariate analysis demonstrated the GG genotype of the rs1800896 polymorphism of the IL-10 gene to be associated with increased risk for PDR (OR=1.99; 95% CI=1.11–3.57; P=0.02), whereas the TT genotype of the rs2243250 polymorphism of the IL-4 gene and the AA genotype of the rs3212227 polymorphism of the IL-12 gene were not independent risk factors for PDR. Our findings suggest that the genetic variations at the IL-10 promoter gene might be a genetic risk factor for PDR in Caucasians with type 2 diabetes.
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Ksiaa Cheikhrouhou L, Sfar I, Aounallah-Skhiri H, Aouadi H, Jendoubi-Ayed S, Ben Abdallah T, Ayed K, Lakhoua-Gorgi Y. Cytokine and apoptosis gene polymorphisms influence the outcome of hepatitis C virus infection. Hepatobiliary Pancreat Dis Int 2011; 10:280-8. [PMID: 21669572 DOI: 10.1016/s1499-3872(11)60047-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is thought to be chronic and the factors leading to viral clearance or persistence are poorly understood. This study was undertaken to investigate the possibility of a significant relationship between the spontaneous clearance or the persistence of hepatitis C virus (HCV) infection and cytokine and apoptosis gene polymorphisms in Tunisian patients on hemodialysis. METHODS Polymorphisms of the genes IL-1 (-889 IL-1alpha, -511 and +3954 IL-1beta, IL-1Ra), IL-18 (-137 and -607), IL-12 (-1188) and Apo1/Fas (-670) were determined by PCR-RFLP, PCR-SSP and PCR-VNTR in 100 healthy blood donors and 100 patients infected with HCV and undergoing hemodialysis. The patients were classified into two groups: G1 consisted of 76 active chronic hepatitis patients (positive for HCV RNA) and G2 consisted of 24 hemodialysed patients who spontaneously eliminated the virus (negative for HCV RNA). RESULTS The frequency of genotype association [-137GC/-607CA] IL-18 was higher in G2 (41.7%) than in G1 (15.8%) (P=0.008; OR=0.26; 95% CI, 0.10-0.73). We also found a higher frequency of the AA genotype of the Apo1/Fas gene in G2 (41.6%) than in G1 (17.5%) (P=0.026; OR=3.49; 95% CI, 1.13-10.69). Adjustment for known covariate factors (age, gender and genotype) confirmed these univariate findings and revealed that the genotype association GC-CA of the (-137 and -607) IL-18 gene and the AA genotype of the Apo1/Fas gene were associated with the clearance of HCV (P=0.041 and 0.017, respectively). CONCLUSION The two genotypes GC-CA of the (-137 and -607) IL-18 polymorphism and the AA genotype of the Apo1/Fas gene influence the outcome of HCV infection in Tunisian patients on hemodialysis.
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Affiliation(s)
- Leila Ksiaa Cheikhrouhou
- Immunology Research Laboratory of Kidney Transplantation and Immunopathology, Charles Nicolle Hospital, Thunis, Tunisia
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Altinova AE, Engin D, Akbay E, Akturk M, Toruner F, Ersoy R, Yetkin I, Arslan M. Association of polymorphisms in the IL-18 and IL-12 genes with susceptibility to Type 1 diabetes in Turkish patients. J Endocrinol Invest 2010; 33:451-4. [PMID: 20061784 DOI: 10.1007/bf03346623] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND Recent studies have indicated that polymorphisms of the interleukin-18 (IL-18) and interleukin- 12 (IL-12) genes are associated with the development of Type 1 diabetes mellitus (T1DM) in some populations, but not all. AIM The present study was designed to examine the roles of polymorphisms in the IL-18 promoter and IL-12p40 with respect to susceptibility to T1DM in Turkish patients. SUBJECTS AND METHODS Ninety-one patients with T1DM and 87 unrelated healthy subjects were included in the study. The IL-18 polymorphisms at positions -607 and -137 were detected by a sequence-specific PCR method. The single nucleotide polymorphism in the IL-12p40 3' untranslated region (3'-UTR) at position +1188 was analyzed by the PCR-restriction fragment length polymorphism (RFPL) method. RESULTS The allelic and genotypic frequencies of the IL-18 and IL-12p40 polymorphisms did not differ significantly between subjects with T1DM and the controls (p>0.05). However, diabetic patients with the -137 (CC) genotype showed a younger onset age compared to patients with the -137 (GG) genotype (p=0.02). In addition, patients with the -607 (CC) genotype had higher levels of glycated hemoglobin (HbA1c) than patients with the -607 (AC) genotype (p=0.004). Furthermore, patients with the IL-12p40 (AC) genotype had higher HbA(1c) levels than patients with the IL-12p40 (AA) genotype (p=0.01). CONCLUSIONS The results of the present study show that the IL- 18 and IL-12p40 polymorphisms may have some effect on the onset age and deterioration of glycemic control in Turkish patients with T1DM.
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Affiliation(s)
- A E Altinova
- Department of Endocrinology and Metabolism, Gazi University Faculty of Medicine, Ankara, Turkey.
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Möller M, Nebel A, van Helden PD, Schreiber S, Hoal EG. Analysis of eight genes modulating interferon gamma and human genetic susceptibility to tuberculosis: a case-control association study. BMC Infect Dis 2010; 10:154. [PMID: 20525402 PMCID: PMC2891757 DOI: 10.1186/1471-2334-10-154] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2010] [Accepted: 06/07/2010] [Indexed: 12/03/2022] Open
Abstract
Background Interferon gamma is a major macrophage-activating cytokine during infection with Mycobacterium tuberculosis, the causative pathogen of tuberculosis, and its role has been well established in animal models and in humans. This cytokine is produced by activated T helper 1 cells, which can best deal with intracellular pathogens such as M. tuberculosis. Based on the hypothesis that genes which regulate interferon gamma may influence tuberculosis susceptibility, we investigated polymorphisms in eight candidate genes. Methods Fifty-four polymorphisms in eight candidate genes were genotyped in over 800 tuberculosis cases and healthy controls in a population-based case-control association study in a South African population. Genotyping methods used included the SNPlex Genotyping System™, capillary electrophoresis of fluorescently labelled PCR products, TaqMan® SNP genotyping assays or the amplification mutation refraction system. Single polymorphisms as well as haplotypes of the variants were tested for association with TB using statistical analyses. Results A haplotype in interleukin 12B was nominally associated with tuberculosis (p = 0.02), but after permutation testing, done to assess the significance for the entire analysis, this was not globally significant. In addition a novel allele was found for the interleukin 12B D5S2941 microsatellite. Conclusions This study highlights the importance of using larger sample sizes when attempting validation of previously reported genetic associations. Initial studies may be false positives or may propose a stronger genetic effect than subsequently found to be the case.
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Affiliation(s)
- Marlo Möller
- Molecular Biology and Human Genetics, MRC Centre for Molecular and Cellular Biology, Faculty of Health Sciences, PO Box 19063, Stellenbosch University, Tygerberg 7505, South Africa.
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Liu L, Xu Y, Liu Z, Chen J, Zhang Y, Zhu J, Liu J, Liu S, Ji G, Shi H, Shen H, Hu Z. IL12 polymorphisms, HBV infection and risk of hepatocellular carcinoma in a high-risk Chinese population. Int J Cancer 2010; 128:1692-6. [PMID: 20521253 DOI: 10.1002/ijc.25488] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2010] [Accepted: 05/27/2010] [Indexed: 12/13/2022]
Abstract
To investigate the association between the potentially functional polymorphisms in IL12A and IL12B, HBV infection and risk of hepatocellular carcinoma in a Chinese population, we genotyped three polymorphisms, rs568408 (3'UTR G>A), rs2243115 (5'UTR T>G) in IL12A and rs3212227 (3'UTR A>C) in IL12B in a case-control study of 869 hepatocellular carcinoma (HCC) cases and 891 cancer-free controls. We found that the IL12A rs568408 GA/AA variant genotypes were associated with a significantly increased risk of HCC (adjusted odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.17-2.00), compared with the wild-type GG homozygote. In the stratified analyses, the increased risk of HCC associated with rs568408 GA/AA was more evident in patients who were negative for HBsAg (adjusted OR = 1.71, 95% CI = 1.23-2.39). However, no significant associations between IL12A rs2243115 T/G, IL12B rs3212227 A/C and risk of HCC were observed. Our findings indicate that IL12A rs568408 may contribute to the risk of HCC and modify HCC risk associated with HBV infection.
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Affiliation(s)
- Li Liu
- Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China
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Morahan G, McKinnon E, Berry J, Browning B, Julier C, Pociot F, James I. Evaluation of IL12B as a candidate type I diabetes susceptibility gene using data from the Type I Diabetes Genetics Consortium. Genes Immun 2009; 10 Suppl 1:S64-8. [PMID: 19956104 PMCID: PMC2805152 DOI: 10.1038/gene.2009.94] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
As part of its efforts to identify genes affecting the risk of type I diabetes (T1D), the Type I Diabetes Genetics Consortium commissioned an extensive survey of variants associated with genes reported earlier to have an association with disease susceptibility. In this report, we present the analysis of a set of single-nucleotide polymorphisms (SNPs) within and flanking the IL12B gene, which encodes the p40 subunit of the cytokines interleukin (IL)-12 and IL-23. No SNP showed individually significant association in the population as a whole. Nevertheless, subjects stratified according to genotype at the earlier reported SNP in the IL12B 3'UTR, rs3212227, confirmed small, but significant, differences in age of disease onset with a relative hazard=0.88 (P=0.005). The protective effect of rs3212227 allele 2 was gender specific (P=0.004 overall and P=0.0003 when unaffected siblings were considered). Among females, the 2.2 genotype was more protective, with relative hazard=0.75. We conclude that while there was no major effect of IL12B polymorphisms on T1D susceptibility in the entire study group, they have an impact on a subset of at-risk individuals.
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Affiliation(s)
- G Morahan
- Centre for Diabetes Research, The Western Australian Institute for Medical Research, and Centre for Medical Research, University of Western Australia, 50 Murray Street, Perth, Western Australia 6000, Australia.
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Hu KF, Huang KC, Ho YP, Lin YC, Ho KY, Wu YM, Yang YH, Tsai CC. Interleukin-10 (-592 C/A) and interleukin-12B (+16974 A/C) gene polymorphisms and the interleukin-10 ATA haplotype are associated with periodontitis in a Taiwanese population. J Periodontal Res 2009; 44:378-85. [PMID: 19210338 DOI: 10.1111/j.1600-0765.2008.01116.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVE Single nucleotide polymorphisms are assumed to be associated with the differential production of cytokines. We evaluated gene polymorphisms of interleukin-10 (-592C>A, -819C>T and -1082G>A) and interleukin-12B (+16974) in patients with chronic periodontitis (n = 145) and generalized aggressive periodontitis (n = 65) in comparison with healthy controls (n = 126). MATERIAL AND METHODS Gene promoter polymorphisms were analyzed by polymerase chain reaction with sequence-specific primers. Genotype and allele frequencies were analyzed using the chi-square test and logistic regression analysis. RESULTS The interleukin-10 -592 polymorphism showed significant differences among the three groups (p = 0.0330). The genotype frequencies of the -592 locus between the chronic periodontitis and healthy control groups were significantly different (AC vs. AA: odds ratio = 0.33). The combination ATA/ATA seemed to be associated with susceptibility to generalized aggressive periodontitis (p = 0.0276). Patients with the composite ATA/ACC were less likely to develop chronic periodontitis (p = 0.0248). The CC genotype of interleukin-12B (+16974) was related to chronic periodontitis (CC vs. AA, p = 0.0211; CC vs. AA+AC, p = 0.0187). The AC heterozygosity of interleukin-12B was significantly lower in chronic periodontitis vs. healthy controls (p = 0.0500). CONCLUSION The interleukin-10 gene polymorphism at position -592C>A may be associated with a lower risk for development of chronic periodontitis. The interleukin-10 haplotype ATA is associated with generalized aggressive periodontitis. On the other hand, interleukin-12B genetic variants at position +16974 are associated with susceptibility to chronic periodontitis.
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Affiliation(s)
- K-F Hu
- Graduate Institute of Dental Sciences (Faculty of Dentistry), College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Chen X, Han S, Wang S, Zhou X, Zhang M, Dong J, Shi X, Qian N, Wang X, Wei Q, Shen H, Hu Z. Interactions of IL-12A and IL-12B Polymorphisms on the Risk of Cervical Cancer in Chinese Women. Clin Cancer Res 2008; 15:400-5. [DOI: 10.1158/1078-0432.ccr-08-1829] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Interleukin-12 p40 gene (IL12B) polymorphisms and the risk of cervical caner in Korean women. Eur J Obstet Gynecol Reprod Biol 2008; 140:71-5. [DOI: 10.1016/j.ejogrb.2008.02.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2007] [Revised: 12/17/2007] [Accepted: 02/19/2008] [Indexed: 12/19/2022]
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Cooper JD, Smyth DJ, Bailey R, Payne F, Downes K, Godfrey LM, Masters J, Zeitels LR, Vella A, Walker NM, Todd JA. The candidate genes TAF5L, TCF7, PDCD1, IL6 and ICAM1 cannot be excluded from having effects in type 1 diabetes. BMC MEDICAL GENETICS 2007; 8:71. [PMID: 18045485 PMCID: PMC2217539 DOI: 10.1186/1471-2350-8-71] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/21/2007] [Accepted: 11/28/2007] [Indexed: 11/10/2022]
Abstract
BACKGROUND As genes associated with immune-mediated diseases have an increased prior probability of being associated with other immune-mediated diseases, we tested three such genes, IL23R, IRF5 and CD40, for an association with type 1 diabetes. In addition, we tested seven genes, TAF5L, PDCD1, TCF7, IL12B, IL6, ICAM1 and TBX21, with published marginal or inconsistent evidence of an association with type 1 diabetes. METHODS We genotyped reported polymorphisms of the ten genes, nonsynonymous SNPs (nsSNPs) and, for the IL12B and IL6 regions, tag SNPs in up to 7,888 case, 8,858 control and 3,142 parent-child trio samples. In addition, we analysed data from the Wellcome Trust Case Control Consortium genome-wide association study to determine whether there was any further evidence of an association in each gene region. RESULTS We found some evidence of associations between type 1 diabetes and TAF5L, PDCD1, TCF7 and IL6 (ORs = 1.05 - 1.13; P = 0.0291 - 4.16 x 10-4). No evidence of an association was obtained for IL12B, IRF5, IL23R, ICAM1, TBX21 and CD40, although there was some evidence of an association (OR = 1.10; P = 0.0257) from the genome-wide association study for the ICAM1 region. CONCLUSION We failed to exclude the possibility of some effect in type 1 diabetes for TAF5L, PDCD1, TCF7, IL6 and ICAM1. Additional studies, of these and other candidate genes, employing much larger sample sizes and analysis of additional polymorphisms in each gene and its flanking region will be required to ascertain their contributions to type 1 diabetes susceptibility.
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Affiliation(s)
- Jason D Cooper
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 OXY, UK
| | - Deborah J Smyth
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 OXY, UK
| | - Rebecca Bailey
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 OXY, UK
| | - Felicity Payne
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 OXY, UK
- Metabolic Disease Group, Sulston Laboratory, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK
| | - Kate Downes
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 OXY, UK
| | - Lisa M Godfrey
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 OXY, UK
| | - Jennifer Masters
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 OXY, UK
- Division of Transfusion Medicine, Department of Haematology, University of Cambridge, East Anglia Blood Centre, Cambridge, CB2 2PT, UK
| | - Lauren R Zeitels
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 OXY, UK
| | - Adrian Vella
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 OXY, UK
- Mayo Clinic College of Medicine, Division of Endocrinology and Metabolism, 200 First ST SW, Rochester, MN55905, USA
| | - Neil M Walker
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 OXY, UK
| | - John A Todd
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 OXY, UK
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Stanilova S, Miteva L, Prakova G. Interleukin-12B-3'UTR polymorphism in association with IL-12p40 and IL-12p70 serum levels and silicosis severity. Int J Immunogenet 2007; 34:193-9. [PMID: 17504509 DOI: 10.1111/j.1744-313x.2007.00680.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Susceptibility to silicosis and to disease severity is in part genetically determined. In this study, the role of IL-12B-3'UTR polymorphism in susceptibility and severity of silicosis and its influence on IL-12p40 and IL-12p70 serum level were investigated. The quantity of IL-12p40 and IL-12p70 was detected by enzyme-linked immunosorbent assay and the genotype of IL-12B was determined using the polymerase chain reaction-restriction fragment-length polymorphism method. We observed elevated IL-12p40 in contrast to IL-12p70 serum levels in a group of 62 silicosis patients compared with both control groups. In severe silicosis patients, we detected the highest IL-12p40 serum levels (129.1 +/- 67.7 pg mL(-1)); lower in patients with the moderate (94 +/- 41.6 pg mL(-1)), whereas in mild silicosis, the IL-12p40 levels (67 +/- 23.5 pg mL(-1)) was similar to these in healthy donors. According to IL-12B polymorphism, increased serum levels were observed in subjects with AA genotype (103.2 +/- 46.9 pg mL(-1)) compared to silicosis patients with AC genotype (82.7 +/- 38.3 pg mL(-1)). No significant differences of genotype and allele frequencies of the 3'UTR polymorphism were observed between silicosis patients and healthy controls. However, the heterozygous genotype was found approximately five times more frequently in patients with mild and moderate (48% and 52%) silicosis compared to patients with severe silicosis (11%), and that IL-12B polymorphism may contribute to silicosis severity rather than to susceptibility. Our data demonstrated that elevated serum IL-12p40, independently of IL-12p70 levels, is associated with severity of silicosis, and suggested that IL-12p40 profibrotic activity may contribute to silicosis severity.
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Affiliation(s)
- S Stanilova
- Department of Molecular Biology, Immunology and Medical Genetics, Faculty of Medicine, Trakia University, Stara Zagora, Bulgaria.
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31
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Morahan G, Kaur G, Singh M, Rapthap CC, Kumar N, Katoch K, Mehra NK, Huang D. Association of variants in theIL12Bgene with leprosy and tuberculosis. ACTA ACUST UNITED AC 2007; 69 Suppl 1:234-6. [PMID: 17445208 DOI: 10.1111/j.1399-0039.2006.773_3.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
There is a great range in outcomes after mycobacterial infections, and this is probably due to individual variation in immune responses. One of the key cytokine regulators of the immune response is interleukin (IL-) 12. The IL12B gene encodes the p40 chain of both IL-12 and IL-23 and it has two major variant sites at which different alleles are associated with increased levels of gene expression and with susceptibility to a range of immune-related diseases. We hypothesized that IL12B variants associated with increased expression would be as associated with susceptibility to persistent mycobacterial infection. We tested this hypothesis by genotyping Indian subjects, having either leprosy or tuberculosis (TB), as well as ethnically matched controls. Subjects with leprosy were less likely to have the 3'UTR genotype associated with lower IL12B expression (P= 0.001). Subjects with TB were not only more likely to have the high-expressing IL12B promoter genotype (P= 0.01) but also more likely to have this in the same haplotype with the high expressing 3'UTR allele (P= 0.0009). These results suggest these infectious diseases may be improved by modulating IL-l2p40 production.
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Affiliation(s)
- G Morahan
- Diabetes Research Centre, Western Australia Institute for Medical Research, Perth, WA, Australia.
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Steck AK, Liu SY, McFann K, Barriga KJ, Babu SR, Eisenbarth GS, Rewers MJ, She JX. Association of the PTPN22/LYP gene with type 1 diabetes. Pediatr Diabetes 2006; 7:274-8. [PMID: 17054449 DOI: 10.1111/j.1399-5448.2006.00202.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVES The goal of this study was to verify the association between type 1 diabetes (T1D) and the protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene in non-Hispanic whites (NHWs) and Hispanics from Colorado. SUBJECTS AND METHODS The C1858T single-nucleotide polymorphism within the PTPN22 gene was genotyped in 753 patients with T1D ascertained from the diabetes clinic at the Barbara Davis Center in Denver and 662 control population. RESULTS Both the PTPN22 CT genotype [odds ratio (OR) = 1.96; p < 0.0001] and TT genotype (OR = 4.41; p = 0.02) were significantly associated with T1D in the NHW population. While the association was stronger in subjects with non-HLA-DR3/4 genotypes than in those with the HLA-DR3/4 genotype, regression analyses did not reveal significant interaction between PTPN22 genotypes and HLA-DR3/4. The strength of the association was similar in males and females, patients diagnosed before and after age 10 yr, and in Hispanics and NHWs. CONCLUSION In this study, we confirm that PTPN22 is associated with T1D in the Colorado population.
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Affiliation(s)
- Andrea K Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Aurora, CO, USA
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Abstract
The evidence that there is clinical heterogeneity of type 1 diabetes is reviewed and the implications for genetic studies are discussed. In the past year, genome-wide linkage analysis of 1435 multiplex families was reported. Additionally, confirmed evidence for association of specific markers at two loci (PTPN22, OAS1) as well as failure to replicate three others (IL12B, SUMO4, PAX4) is discussed. Some common themes are identified and suggestions for improvements are made. We look forward to the results from genome-wide association studies.
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Affiliation(s)
- Andrew D Paterson
- Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto Medical Discovery East Tower, Toronto, Ontario M5G 1L7, Canada.
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Yang JM, Nagasaka S, Yatagai T, Nakamura T, Kusaka I, Ishikawa SE, Saito T, Ishibashi S. Interleukin-12p40 gene (IL-12B) polymorphism and Type 1 diabetes mellitus in Japanese: possible role in subjects without having high-risk HLA haplotypes. Diabetes Res Clin Pract 2006; 71:164-9. [PMID: 16005098 DOI: 10.1016/j.diabres.2005.05.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2004] [Revised: 05/02/2005] [Accepted: 05/26/2005] [Indexed: 11/25/2022]
Abstract
The present study was undertaken to clarify a role of interleukin-12p40 gene (IL-12B) polymorphism, located on chromosome 5q33-34 (IDDM 18), in Japanese subjects with Type 1 diabetes mellitus (T1DM) and autoimmune thyroid diseases (AITD). In 179 subjects with T1DM, 166 with AITD (128 with Graves' disease and 38 with Hashimoto's thyroiditis) and 115 healthy control subjects, the IL-12B 3'UTR A-C polymorphism was determined by PCR-RFLP method. In T1DM subjects, the genotype was also analyzed in relation to human leukocyte antigen (HLA)-DRB1-DQB1 haplotype status. There was a weak difference in the distribution of the genotype frequency between T1DM and control subjects, and the C allele frequency was higher in T1DM subjects (P<0.05). In 68 T1DM subjects without having high-risk HLA haplotypes to T1DM in this population, the genotype distribution and C allele frequency was significantly different from control subjects without high-risk HLA haplotypes (P<0.01), and from T1DM subjects with high-risk HLA haplotypes (n=111) (P<0.05). There was no difference in the genotype and allele frequencies between AITD and control subjects. In conclusion, the IL-12B 3'UTR A-C polymorphism did not seem to play a major role on genetic susceptibility to T1DM and AITD in Japanese, although the polymorphism conferred susceptibility in T1DM subjects without having high-risk HLA haplotypes. The IL-12B 3'UTR A-C polymorphism would be considered as a supplementary risk factor to T1DM in conjunction with HLA haplotypes.
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Affiliation(s)
- Jian Mei Yang
- Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, Yakushiji 3311-1, Minamikawachi, Tochigi 329-0498, Japan
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35
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Stanilova S, Miteva L. Taq-I polymorphism in 3'UTR of the IL-12B and association with IL-12p40 production from human PBMC. Genes Immun 2005; 6:364-6. [PMID: 15858599 DOI: 10.1038/sj.gene.6364213] [Citation(s) in RCA: 57] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
A wide array of studies has demonstrated differences in genotype and allele frequencies of cytokine gene polymorphisms depending on ethnicity and race. In this study, the frequency of Taq-I polymorphism in 3' untranslated region of IL-12B was investigated in two Bulgarian ethnic groups-Bulgarians and Turkish minority. No significant differences of genotype and allele frequencies were observed between these groups. Genotype distribution in the total group of Bulgarian citizens was: AA (61%), CA (32%) and CC (7%), and the allele frequency of 16974 A allele was 0.77. We also evaluated whether this polymorphism affects IL-12p40 production from human PBMC after stimulation. We demonstrated that association between genotype and IL-12p40 production by stimulated PBMC depends on the stimuli used. Our results indicated a significantly decreased IL-12 p40 secretion for the following order of genotypes: AA>CA>CC, after stimulation of PBMC with C3-binding glycoprotein (C3bgp) in contrast to lipopolysaccharide, phytohaemagglutinin and pokeweed mitogen.
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Affiliation(s)
- S Stanilova
- Department of Molecular Biology, Immunology and Genetics, Faculty of Medicine, Trakia University, Stara Zagora, Bulgaria.
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36
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Santiago JL, Martínez A, de La Calle H, Fernández-Arquero M, de La Concha EG, Urcelay E. Th1 Cytokine Polymorphisms in Spanish Patients With Type 1 Diabetes. Hum Immunol 2005; 66:897-902. [PMID: 16216674 DOI: 10.1016/j.humimm.2005.06.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2005] [Indexed: 11/18/2022]
Abstract
Several polymorphisms in regions where Th1 cytokines (IL12B and IFNG genes) are located were analyzed in 303 Spanish subjects with type 1 diabetes and compared with a control cohort (n = 548). Both groups comprised residents of the Madrid area. The haplotype frequencies were estimated by the expectation-maximization algorithm, and p values were corrected by the number of haplotypes taken into account in the study. Two haplotypes were significantly associated with the disease, one in the IL12B region (D5S2038*8/D5S1352*2/SNP1188C; OR = 3.01, p(c) = 0.0255) and another involved the IFNGgene (D12S313*9/IFNG*1; OR = 1.58, p(c) = 0.0217). Furthermore, a protective IL12B haplotype was found (D5S2038*4/D5S1352*1/SNP1188A; OR = 0.40, p(c) = 0.0405). No association was found for any of IL12B and IFNG markers individually.
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Affiliation(s)
- José L Santiago
- Immunology Department, Hospital Universitario San Carlos, Madrid, Spain
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37
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Windsor L, Morahan G, Huang D, McCann V, Jones T, James I, Christiansen FT, Price P. Alleles of the IL12B 3'UTR associate with late onset of type 1 diabetes. Hum Immunol 2005; 65:1432-6. [PMID: 15603869 DOI: 10.1016/j.humimm.2004.09.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2004] [Revised: 08/28/2004] [Accepted: 09/09/2004] [Indexed: 10/26/2022]
Abstract
Carriage of a polymorphism in the 3'untranslated region of the IL12B gene encoding IL-12p40 was investigated in subjects with type 1 diabetes mellitus stratified by age at diagnosis (n = 648) and compared with a population-based control cohort (n = 246) residing in Western Australia. DNA samples were genotyped by polymerase chain reaction-restriction fragment length polymorphism or pyrosequencing. The C allele was more common in patients diagnosed after age 16 years than in controls (29% vs 17%, OR = 2.0, 95% CI = 1.4-2.7, p = 0.00003) or than in patients diagnosed when younger age 16 years (29% vs 22%, OR = 1.4, 95% CI = 1.1-1.9, p = 0.01). This reflected increases in homozygous and heterozygous carriage of the C allele. Heterozygosity was associated with a delayed disease in the late-onset diabetics (p = 0.005; Student's t-test). The effects of IL12B 3'untranslated region alleles on type 1 diabetes mellitus may reflect different levels of p40 available to form p40 homodimer, IL-12 (p35p40), and IL-23 (p19p40).
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Affiliation(s)
- Lydia Windsor
- School of Surgery and Pathology, University of Western Australia; Nedlands, Australia
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38
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Nieters A, Yuan JM, Sun CL, Zhang ZQ, Stoehlmacher J, Govindarajan S, Yu MC. Effect of cytokine genotypes on the hepatitis B virus-hepatocellular carcinoma association. Cancer 2005; 103:740-8. [PMID: 15643599 DOI: 10.1002/cncr.20842] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND In Southern Guangxi, China, chronic infection with the hepatitis B virus (HBV) acquired during the perinatal period from carrier mothers is a primary cause of hepatocellular carcinoma. However, only a minority of HBV carriers eventually develop hepatocellular carcinoma. The authors hypothesized that cytokine genotypes may be important codeterminants of the risk of HBV-related hepatocellular carcinoma. METHODS The authors examined the correlation between polymorphisms in T-helper 1 (Th1) and Th2 cytokine genes among a group of 250 patients with incident hepatocellular carcinoma (cases) and a group of 250 hospital controls who were matched individually to the index case by age, gender, ethnicity, residence, and month of hospital admission in the city of Nanning, Guangxi, China. RESULTS Relative to the putative high-activity genotypes, each individual low-activity genotype of interferon gamma, interleukin 12 (IL12), and IL18 was associated with a statistically nonsignificant increase (40-60%) in the risk of hepatocellular carcinoma. This risk increased with increasing numbers of low-activity Th1 genotypes after adjusting for potential confounders (2-sided P value for trend=0.04). Conversely, individual Th2 (IL4, IL10) low-activity genotypes were associated with a statistically nonsignificant reduced risk of hepatocellular carcinoma. This risk decreased with increasing number of low-activity Th2 genotypes after adjusting for potential confounders (2-sided P value for trend=0.01). Individuals who had the maximum number (i.e., 3) of low-activity Th1 genes and the minimum number (i.e., 0) of low-activity Th2 genes showed a relative risk of 20.0 (95% confidence interval, 1.7-235.0). CONCLUSIONS Diminished cell-mediated immune response, which is controlled genetically, appeared to be an important risk determinant of HBV-related hepatocellular carcinogenesis.
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Affiliation(s)
- Alexandra Nieters
- Department of Clinical Epidemiology, German Cancer Research Center, Heidelberg, Germany.
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39
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Yin LM, Zhu WF, Wei L, Xu XY, Sun DG, Wang YB, Fan WM, Yu M, Tian XL, Wang QX, Gao Y, Zhuang H. Association of interleukin-12 p40 gene 3’-untranslated region polymorphism and outcome of HCV infection. World J Gastroenterol 2004; 10:2330-3. [PMID: 15285014 PMCID: PMC4576283 DOI: 10.3748/wjg.v10.i16.2330] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate the effect of interleukin-12 p40 gene (IL12B) 3’-untranslated region polymorphism on the outcome of HCV infection.
METHODS: A total of 133 patients who had been infected with HCV for 12-25 (18.2 ± 3.8) years, were enrolled in this study. Liver biochemical tests were performed with an automated analyzer and HCV RNA was detected by fluorogenic quantitative polymerase chain reaction. B-mode ultrasound was used for liver examination. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for the detection of IL12B (1188A/C) polymorphism.
RESULTS: Self-limited infection was associated with AC genotype (OR = 3.48; P = 0.001) and persistent infection was associated with AA genotype (OR = 0.34; P = 0.014) at site 1188 of IL12B. In patients with persistent HCV infection, no significant differences were found regarding the age, gender, duration of infection and biochemical characteristics (P > 0.05). According to B-mode ultrasound imaging and clinical diagnosis, patients with persistent infection were divided into groups based on the severity of infection. No significant differences were found in the frequency of IL-12 genotype (1188A/C) between different groups (P > 0.05).
CONCLUSION: The polymorphism of IL12B (1188A/C) appears to have some influence on the outcome of HCV infection.
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Affiliation(s)
- Li-Min Yin
- Department of Microbiology, School of Basic Medical Sciences, Peking University, Beijing 100083, China
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Burgner D, Rockett K, Ackerman H, Hull J, Usen S, Pinder M, Kwiatkowski DP. Haplotypic relationship between SNP and microsatellite markers at the NOS2A locus in two populations. Genes Immun 2004; 4:506-14. [PMID: 14551604 DOI: 10.1038/sj.gene.6364022] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The density of genetic markers required for successful association mapping of complex diseases depends on linkage disequilibrium (LD) between non-functional markers and functional variants. The haplotypic relationship between stable markers and potentially unstable but highly informative markers (e.g. microsatellites) indicates that LD might be maintained over considerable genetic distance in non-African populations, supporting the use of such 'mixed marker haplotypes' in LD-based mapping, and allowing inferences to be drawn about human origins. We investigated sequence variation in the proximal 2.6 kb of the inducible nitric oxide synthase (NOS2A) promoter and the relationship between SNP haplotypes and a pentanucleotide microsatellite (the 'NOS2A(-2.6) microsatellite') in Gambians and UK Caucasians. UK Caucasians exhibited a subset of sequence diversity observed in Gambians, sharing four of 11 SNPs and a similar haplotypic structure. Five SNPs were found in the sequence of interspersed repetitive DNA elements. In both populations, there was dramatic loss of LD between SNP haplotypes and microsatellite alleles across a very short physical distance, suggesting a high intrinsic mutation rate of the NOS2A(-2.6) microsatellite, the SNP haplotypes are relatively ancient, or that this was a region of frequent recombination. Understanding locus- and population-specific LD is essential when designing and interpreting genetic association studies.
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Affiliation(s)
- D Burgner
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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41
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Abstract
Type 1 diabetes is an autoimmune disease with a complex polygenic inheritance. Until recently, only three susceptibility genes had been reproducibly identified, namely HLA, INS-VNTR, and CTLA4. During the past 7 years, a number of new putative susceptibility genes have been isolated from both human and animal models of the disease. We present eight genes implicated in type 1 diabetes etiology and discuss them in relation to the pathogenesis of the disease: VDR, IL6, IL12B, AIRE, FOXP3, B2m, Cblb, and Lyp/Ian4l1.
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Affiliation(s)
- Lars Hornum
- Type 1 Pharmacology, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark.
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Tabone T, Morahan G. Definition of polymorphisms in the gene encoding the interleukin-12 receptor B1 subunit: testing linkage disequilibrium with Type I diabetes susceptibility. Genes Immun 2003; 4:222-7. [PMID: 12700597 DOI: 10.1038/sj.gene.6363948] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The cytokine interleukin (IL)-12 is bound by a heterodimeric receptor and mediates a range of immunological activities, in particular, favouring the development of uncommitted T cells to the Th1 phenotype. Genes encoding elements of the IL-12 pathway are therefore good candidates for mediating susceptibility or resistance to a range of immune disorders, including Type I diabetes. We made a systematic search for variants in the human gene encoding the low-affinity IL-12 receptor, IL12RB1. Four single-nucleotide polymorphisms and two microsatellite polymorphisms were defined. We also tested these IL12RB1 alleles for involvement in Type I diabetes susceptibility, testing 131 families. Although suggestive evidence for linkage to a susceptibility gene was found, none of the IL12RB1 variants we defined demonstrated preferential transmission in these families.
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Affiliation(s)
- T Tabone
- The Walter and Eliza Hall Institute of Medical Research, IG Royal Parade, Parville, Victoria, Australia
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Abstract
Recent applications of the genetic characterisation of autoimmunity in humans and in animal models have allowed the further mapping of many disease loci and, in some cases, the identification of disease genes. New approaches to the analysis of mapping, characterisation and identification of susceptibility genes have also been developed.
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Affiliation(s)
- Grant Morahan
- The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria 3050, Australia
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44
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Current literature in diabetes. Diabetes Metab Res Rev 2002; 18:491-8. [PMID: 12469363 DOI: 10.1002/dmrr.248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Morahan G, Huang D, Wu M, Holt BJ, White GP, Kendall GE, Sly PD, Holt PG. Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children. Lancet 2002; 360:455-9. [PMID: 12241719 DOI: 10.1016/s0140-6736(02)09676-9] [Citation(s) in RCA: 138] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Severe asthma is a frequent cause of hospital admission, especially among children. The main environmental triggers of airway inflammation in asthma are viruses and aeroallergens. These agents elicit reciprocal immune responses, characterised by production of T helper 1 and T helper 2 cytokines, respectively. There is no genetic explanation for how hyper-responsiveness to these disparate environmental stimuli develops among individuals with asthma. Our aim was to assess relation between an IL12B promoter polymorphism and asthma. METHODS We did a cohort study in which we initially genotyped 411 6-year olds for the IL12B promoter polymorphism. We then assessed the relation between this polymorphism and asthma severity. A further 85 asthmatic children in an additional sample of 433 children from the same cohort were then assessed to confirm these findings. We also examined in-vitro interleukin-12 responses in a subgroup of individuals. FINDINGS Heterozygosity for the IL12B promoter polymorphism was observed in 76% (16) of atopic and non-atopic individuals with severe asthma in the initial sample. By comparison, heterozygotes comprised only 31% (17) of the moderate asthma group, and 48% (20) of individuals with mild asthma were heterozygous, as were unaffected controls. These findings were confirmed in the second sample (overall p<0.0001). Our data suggest that IL12B promoter heterozygosity contributes to asthma severity rather than susceptibility per se. The severity-predisposing genotype was associated with reduced interleukin 12 p40 gene transcription and decreased interleukin 12 p70 secretion. INTERPRETATION Interleukin 12 plays a key part in antagonism of T helper 2 differentiation, and in induction of antiviral host defense. Genetically determined attenuation of interleukin-12 response capacity would, therefore, provide a plausible common immunological pathway to disease severity for the two major forms of asthma.
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Affiliation(s)
- Grant Morahan
- The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria 3050, Australia
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