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Rutledge SM, Soper ER, Ma N, Pejaver V, Friedman SL, Branch AD, Kenny EE, Belbin GM, Abul-Husn NS. Association of HSD17B13 and PNPLA3 With Liver Enzymes and Fibrosis in Hispanic/Latino Individuals of Diverse Genetic Ancestries. Clin Gastroenterol Hepatol 2023; 21:2578-2587.e11. [PMID: 36610497 DOI: 10.1016/j.cgh.2022.12.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 11/23/2022] [Accepted: 12/13/2022] [Indexed: 01/09/2023]
Abstract
BACKGROUND & AIMS Genetic variants affecting liver disease risk vary among racial and ethnic groups. Hispanics/Latinos in the United States have a high prevalence of PNPLA3 I148M, which increases liver disease risk, and a low prevalence of HSD17B13 predicted loss-of-function (pLoF) variants, which reduce risk. Less is known about the prevalence of liver disease-associated variants among Hispanic/Latino subpopulations defined by country of origin and genetic ancestry. We evaluated the prevalence of HSD17B13 pLoF variants and PNPLA3 I148M, and their associations with quantitative liver phenotypes in Hispanic/Latino participants from an electronic health record-linked biobank in New York City. METHODS This study included 8739 adult Hispanic/Latino participants of the BioMe biobank with genotyping and exome sequencing data. We estimated the prevalence of Hispanic/Latino individuals harboring HSD17B13 and PNPLA3 variants, stratified by genetic ancestry, and performed association analyses between variants and liver enzymes and Fibrosis-4 (FIB-4) scores. RESULTS Individuals with ancestry from Ecuador and Mexico had the lowest frequency of HSD17B13 pLoF variants (10%/7%) and the highest frequency of PNPLA3 I148M (54%/65%). These ancestry groups had the highest outpatient alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and the largest proportion of individuals with a FIB-4 score greater than 2.67. HSD17B13 pLoF variants were associated with reduced ALT level (P = .002), AST level (P < .001), and FIB-4 score (P = .045). PNPLA3 I148M was associated with increased ALT level, AST level, and FIB-4 score (P < .001 for all). HSD17B13 pLoF variants mitigated the increase in ALT conferred by PNPLA3 I148M (P = .006). CONCLUSIONS Variation in HSD17B13 and PNPLA3 variants across genetic ancestry groups may contribute to differential risk for liver fibrosis among Hispanic/Latino individuals.
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Affiliation(s)
- Stephanie M Rutledge
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Emily R Soper
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Ning Ma
- Division of Liver Medicine, Icahn School of Medicine Mount Sinai, New York, New York
| | - Vikas Pejaver
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Scott L Friedman
- Division of Liver Medicine, Icahn School of Medicine Mount Sinai, New York, New York
| | - Andrea D Branch
- Division of Liver Medicine, Icahn School of Medicine Mount Sinai, New York, New York
| | - Eimear E Kenny
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Division of General Internal Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Gillian M Belbin
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York; Division of General Internal Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Noura S Abul-Husn
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
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He J, Du C, Peng X, Hong W, Qiu D, Qiu X, Zhang X, Qin Y, Zhang Q. Hepatocyte nuclear factor 1A suppresses innate immune response by inducing degradation of TBK1 to inhibit steatohepatitis. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.05.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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Hu J, Xu Y, He Z, Zhang H, Lian X, Zhu T, Liang C, Li J. Increased risk of cerebrovascular accident related to non-alcoholic fatty liver disease: a meta-analysis. Oncotarget 2017; 9:2752-2760. [PMID: 29416808 PMCID: PMC5788676 DOI: 10.18632/oncotarget.22755] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 10/27/2017] [Indexed: 12/19/2022] Open
Abstract
Recent published studies on the association between non-alcoholic fatty liver disease (NAFLD) and cerebrovascular accident (CVA) risk have yielded conflicting findings. The aim of our study was to identify the potential association by pooling all available publications. A total of nine independent studies were included into our study. The pooled odd ratio (OR) with 95% confidence interval (95% CI) was calculated to weigh the strength for the relationship between NAFLD and CVA risk. We also conducted stratified analyses by study design, ethnicity and disease classification for further elucidation. The pooled results of the present meta-analysis showed that NAFLD was related to increased risk of CVA (OR = 2.32, 95% CI 1.84–2.93, P < 0.001). Besides, NAFLD is associated with increased risk of CVA among both Caucasians (OR = 2.27, 95% CI 1.77–2.90, P < 0.001) and Asians (OR = 2.81, 95% CI 1.43–5.51, P = 0.003). Moreover, the significant association was also observed in case-control studies (OR = 2.73, 95% CI 1.67–4.48, P < 0.001) and cohort studies (OR = 2.22, 95% CI 1.71–2.89, P < 0.001), respectively. In addition, NAFLD was shown to correlate with increased risk of cerebral hemorrhage (OR = 1.85, 95% CI 1.05–3.27, P = 0.034) and the ischemic stroke (OR = 2.51, 95% CI 1.92–3.28, P < 0.001). In conclusion, our findings firstly provide strong evidence for a risk effect of NAFLD on CVA development.
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Affiliation(s)
- Jianping Hu
- Department of General Surgery, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Yong Xu
- Department of Nephrology, Huai'an Second People's Hospital and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
| | - Zemin He
- Department of General Surgery, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Hui Zhang
- Department of General Surgery, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Xiaoqing Lian
- Department of Cardiovasology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Tiantian Zhu
- Department of Cardiovasology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Caihong Liang
- Department of Cardiovasology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Jun Li
- Department of General Surgery, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
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Firouzabadi SG, Kariminejad R, Vameghi R, Darvish H, Ghaedi H, Banihashemi S, Firouzkouhi Moghaddam M, Jamali P, Mofidi Tehrani HF, Dehghani H, Narooie-Nejad M, Jamshidi J, Tafakhori A, Sadabadi S, Najmabadi H, Behjati F. Copy Number Variants in Patients with Autism and Additional Clinical Features: Report of VIPR2 Duplication and a Novel Microduplication Syndrome. Mol Neurobiol 2016; 54:7019-7027. [PMID: 27796743 DOI: 10.1007/s12035-016-0202-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 10/11/2016] [Indexed: 10/20/2022]
Abstract
Autism is a common neurodevelopmental disorder estimated to affect 1 in 68 children. Many studies have shown the role of copy number variants (CNVs) as a major contributor in the etiology of autism with the overall detection rate of about 10-15 % and over 20 % when syndromic forms of autism exist. In this study, we used array CGH to identify CNVs in 15 Iranian patients with autism. To elevate our diagnostic yield, we selected the sporadic patients who had additional clinical features including intellectual disability (ID), craniofacial anomaly, and seizure. Six out of 15 patients showed clinically relevant CNVs including pathogenic and likely pathogenic copy number gains or losses. We report a novel gene duplication syndrome (10q21.2q21.3 microduplication) and present a new evidence for VIPR2 duplication, as a candidate gene for autism. Furthermore, we describe the first manifesting carrier female with deletion of SLC6A8 and BCAP31 genes on Xq28. Our findings suggest that there might be a higher prevalence of clinically significant CNVs in patients with autism and additional clinical manifestations. The CNV analysis in such patients could lead to the discovery of novel syndromes as well as unraveling the etiology of autism.
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Affiliation(s)
| | | | - Roshanak Vameghi
- Pediatric Neurorehabilitation Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Hossein Darvish
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Ghaedi
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Susan Banihashemi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Mahboubeh Firouzkouhi Moghaddam
- Child and Adolescent Psychiatry Department, Zahedan University of Medical Sciences, Zahedan, Iran.,Research Center for Children and Adolescents Health, Zahedan University of Medical Sciences, Zahedan, Iran
| | | | | | - Hossein Dehghani
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Mehrnaz Narooie-Nejad
- Genetics of Non-communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Javad Jamshidi
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
| | - Abbas Tafakhori
- Department of Neurology, School of Medicine, Imam Khomeini Hospital and Iranian Center of Neurological Research, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeid Sadabadi
- Bahar Education and Rehabilitation Center for the handicapped, Tehran, Iran
| | - Hossein Najmabadi
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.,Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran
| | - Farkhondeh Behjati
- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
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Fleischman MW, Budoff M, Zeb I, Li D, Foster T. NAFLD prevalence differs among hispanic subgroups: The multi-ethnic study of atherosclerosis. World J Gastroenterol 2014; 20:4987-4993. [PMID: 24803810 PMCID: PMC4009531 DOI: 10.3748/wjg.v20.i17.4987] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare prevalence rates of non-alcoholic fatty liver disease (NAFLD) between Hispanics of Mexican origin and Hispanics of Dominican and Puerto Rican origin.
METHODS: We evaluated prevalence rates of NAFLD between the two largest sub-populations of Hispanics in the United States; Hispanics of Mexican origin and Hispanics of Caribbean origin (Dominican and Puerto Rican), in the multi-ethnic study of atherosclerosis (MESA) cohort. MESA is a large, population based, multi-center cohort study comprised of 6814 healthy Caucasian, African-American, Hispanic, and Asian men and women aged 45-84. We utilized the baseline serum, anthropometric and radiographic measurements obtained between 2000 and 2002. NAFLD was measured via computed tomography scan and was defined as liver/spleen attenuation ratio < 1.
RESULTS: There were 788 Hispanic participants included in the study after exclusions. The prevalence of NAFLD was 29% (n = 225). Hispanics of Mexican origin had a significantly higher prevalence of NAFLD (33%), compared to Hispanics of Dominican origin (16%), (P < 0.01) and Hispanics of Puerto Rican origin (18%), (P < 0.01). After controlling for age, sex, BMI, waist circumference, hypertension, serum HDL, triglyceride and CRP level and insulin resistance, Hispanics of Mexican origin remained significantly more likely to have NAFLD than those of Dominican and Puerto Rican origin.
CONCLUSION: United States Hispanics of Mexican origin have a significantly higher prevalence of NAFLD when compared to United States Hispanics of Dominican or Puerto Rican origin after controlling for known risk factors. Care should be taken when performing risk assessment in Hispanic populations not to make assumptions of homogeneity.
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Williams CD, Stengel J, Asike MI, Torres DM, Shaw J, Contreras M, Landt CL, Harrison SA. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011; 140:124-31. [PMID: 20858492 DOI: 10.1053/j.gastro.2010.09.038] [Citation(s) in RCA: 1613] [Impact Index Per Article: 115.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2010] [Revised: 08/03/2010] [Accepted: 09/09/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Prevalence of nonalcoholic fatty liver disease (NAFLD) has not been well established. The purpose of this study was to prospectively define the prevalence of both NAFLD and nonalcoholic steatohepatitis (NASH). METHODS Outpatients 18 to 70 years old were recruited from Brooke Army Medical Center. All patients completed a baseline questionnaire and ultrasound. If fatty liver was identified, then laboratory data and a liver biopsy were obtained. RESULTS Four hundred patients were enrolled. Three hundred and twenty-eight patients completed the questionnaire and ultrasound. Mean age (range, 28-70 years) was 54.6 years (7.35); 62.5% Caucasian, 22% Hispanic, and 11.3% African American; 50.9% female; mean body mass index (BMI) (calculated as kg/m(2)) was 29.8 (5.64); and diabetes and hypertension prevalence 16.5% and 49.7%, respectively. Prevalence of NAFLD was 46%. NASH was confirmed in 40 patients (12.2% of total cohort, 29.9% of ultrasound positive patients). Hispanics had the highest prevalence of NAFLD (58.3%), then Caucasians (44.4%) and African Americans (35.1%). NAFLD patients were more likely to be male (58.9%), older (P = .004), hypertensive (P < .00005), and diabetic (P < .00005). They had a higher BMI (P < .0005), ate fast food more often (P = .049), and exercised less (P = 0.02) than their non-NAFLD counterparts. Hispanics had a higher prevalence of NASH compared with Caucasians (19.4% vs 9.8%; P = .03). Alanine aminotransferase, aspartate aminotransferase, BMI, insulin, Quantitative Insulin-Sensitivity Check Index, and cytokeratin-18 correlated with NASH. Among the 54 diabetic patients, NAFLD was found in 74% and NASH in 22.2%. CONCLUSION Prevalence of NAFLD and NASH is higher than estimated previously. Hispanics and patients with diabetes are at greatest risk for both NAFLD and NASH.
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Affiliation(s)
- Christopher D Williams
- Gastroenterology and Hepatology Service, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, Texas 78234, USA
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Weber SN, Wasmuth HE. Liver fibrosis: from animal models to mapping of human risk variants. Best Pract Res Clin Gastroenterol 2010; 24:635-46. [PMID: 20955966 DOI: 10.1016/j.bpg.2010.07.013] [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] [Received: 04/29/2010] [Revised: 07/25/2010] [Accepted: 07/28/2010] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is the sequel of chronic liver diseases and the main reason for increased mortality in affected patients. The extent of liver fibrosis displays great interindividual variation, even after controlling for exogenous factors. Thus, host genetic factors are considered to play an important role in the process of liver scarring. From a genetic perspective, liver fibrosis is a complex trait with many genes contributing to the expression of the phenotype. In genetically manipulated and inbred animals several risk loci for liver fibrosis have been identified. Some of these loci have been replicated in case-control studies of patients with hepatitis C infection. In humans, genetic risk loci were identified by single marker studies, haplotype studies or the combination of single markers. Recently, the first genome-wide association studies have also been performed in patients with liver diseases. Some of the identified gene variants have been functionally characterized in vitro, thereby opening the potential for novel therapeutic approaches and risk stratification.
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Affiliation(s)
- Susanne N Weber
- Department of Medicine II, Saarland University Hospital, Homburg, Germany
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Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis 2009; 13:511-31. [PMID: 19818302 DOI: 10.1016/j.cld.2009.07.005] [Citation(s) in RCA: 290] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition in many parts of the world. This article describes the epidemiology and natural history of this disorder. It also describes current diagnostic and treatment methods and describes future implications NAFLD may have.
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Affiliation(s)
- Curtis K Argo
- Division of Gastroenterology and Hepatology, University of Virginia Health System, 1335 Lee Street, MSB 2091, Box 800708, Charlottesville, VA 22908-0708, USA.
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