Associations of 17-beta dehydrogenase 13 variants with liver histology in Chinese patients with MAFLD

Background and objective: In Europeans, variants in the hydroxysteroid 17-beta dehydrogenase 13 ( HSD17B13 ) gene impact the liver histology of metabolic associated fatty liver disease (MAFLD). The impact of these variants in ethnic Chinese is unknown. The aim of this study was to investigate the potential associations in Chinese patients. Methods: 427 Han Chinese with biopsy-confirmed MAFLD were enrolled. Two single nucleotide polymorphisms in HSD17B13 were genotyped - rs72613567 and rs6531975. Logistic regression was used to test the association between the SNPs and liver histology. Results: In our cohort, the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis [OR = 2.93 (1.20-7.17), P = 0.019 for the additive model; OR = 3.32 (1.39-7.91), P = 0.007 for the recessive model], an inverse association as compared to the results from European cohorts. In contrast, we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant [OR = 0.48 (0.24-0.98), P = 0.043 for the additive model; OR = 0.62 (0.40-0.94), P = 0.025 for the dominant model]. HSD17B13 variants were only associated with fibrosis but not other histological features. Furthermore, HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis. Conclusions: The HSD17B13 rs72613567 variant is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans. This data exemplifies the need for studying diverse populations in genetic studies in order to fine map GWAS signals.

[1]  M. Zheng,et al.  Effect of PNPLA3 polymorphism on diagnostic performance of various noninvasive markers for diagnosing and staging nonalcoholic fatty liver disease , 2020, Journal of gastroenterology and hepatology.

[2]  C. Datz,et al.  Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers , 2020, Hepatology.

[3]  V. Ratziu,et al.  Why do so many NASH trials fail? , 2020, Gastroenterology.

[4]  V. Wong,et al.  A new definition for metabolic associated fatty liver disease: an international expert consensus statement. , 2020, Journal of hepatology.

[5]  A. Sanyal,et al.  MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease. , 2020, Gastroenterology.

[6]  G. Marchesini,et al.  Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation , 2020, Hepatology.

[7]  D. Zeng,et al.  Association of HSD17B13 rs72613567:TA with non‐alcoholic fatty liver disease in Hispanics/Latinos , 2020, Liver international : official journal of the International Association for the Study of the Liver.

[8]  American Diabetes Association.  1. Improving Care and Promoting Health in Populations: Standards of Medical Care in Diabetes—2020 , 2019, Diabetes Care.

[9]  M. Trauner,et al.  Impact of HSD17B13 rs72613567 genotype on hepatic decompensation and mortality in patients with portal hypertension , 2019, Liver international : official journal of the International Association for the Study of the Liver.

[10]  W. Syn,et al.  Association of IFNL3 rs12979860 polymorphism with HCV-related hepatocellular carcinoma susceptibility in a Chinese population , 2019, Clinical and experimental gastroenterology.

[11]  J. George,et al.  Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology , 2019, Nature Reviews Gastroenterology & Hepatology.

[12]  Hongliang Li,et al.  Unexpected Rapid Increase in the Burden of NAFLD in China From 2008 to 2018: A Systematic Review and Meta‐Analysis , 2019, Hepatology.

[13]  G. Saglietti,et al.  Severity of Nonalcoholic Fatty Liver Disease in Type 2 Diabetes Mellitus: Relationship between Nongenetic Factors and PNPLA3/HSD17B13 Polymorphisms , 2019, Diabetes & metabolism journal.

[14]  J. George,et al.  Genetic Insights for Drug Development in NAFLD. , 2019, Trends in pharmacological sciences.

[15]  E. Speliotes,et al.  17‐Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease , 2019, Hepatology.

[16]  W. Almawi,et al.  TLR3 and TLR4 SNP variants in the liver disease resulting from hepatitis B virus and hepatitis C virus infection , 2018, British journal of biomedical science.

[17]  S. Sookoian,et al.  Splice variant rs72613567 prevents worst histologic outcomes in patients with nonalcoholic fatty liver disease[S] , 2018, Journal of Lipid Research.

[18]  Alicia R. Martin,et al.  Current clinical use of polygenic scores will risk exacerbating health disparities , 2018 .

[19]  E. Kashuba,et al.  Impact of the Uridine–Cytidine Kinase Like-1 Protein and IL28B rs12979860 and rs8099917 SNPs on the Development of Hepatocellular Carcinoma in Cirrhotic Chronic Hepatitis C Patients—A Pilot Study , 2018, Medicina.

[20]  Alexander E. Lopez,et al.  A Protein‐Truncating HSD17B13 Variant and Protection from Chronic Liver Disease , 2018, The New England journal of medicine.

[21]  M. Eslam,et al.  Genetics and epigenetics of NAFLD and NASH: Clinical impact. , 2018, Journal of hepatology.

[22]  T. Berg,et al.  TLL1 rs17047200 Increases the Risk of Fibrosis Progression in Caucasian Patients With Chronic Hepatitis C. , 2017, Gastroenterology.

[23]  H. Yoshiji,et al.  Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection. , 2017, Gastroenterology.

[24]  Linlin Lu,et al.  Role of NCAN rs2228603 polymorphism in the incidence of nonalcoholic fatty liver disease: a case-control study , 2016, Lipids in Health and Disease.

[25]  Xu Lin,et al.  Lack of association between SREBF-1c gene polymorphisms and risk of non-alcoholic fatty liver disease in a Chinese Han population , 2016, Scientific Reports.

[26]  E. Tsochatzis,et al.  The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). , 2016, Metabolism: clinical and experimental.

[27]  L. Henry,et al.  Global epidemiology of nonalcoholic fatty liver disease—Meta‐analytic assessment of prevalence, incidence, and outcomes , 2016, Hepatology.

[28]  Linlin Lu,et al.  Association Between LYPLAL1 rs12137855 Polymorphism With Ultrasound-Defined Non-Alcoholic Fatty Liver Disease in a Chinese Han Population , 2015, Hepatitis monthly.

[29]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[30]  Shan Li,et al.  Genetic polymorphisms in Toll-like receptor 3 gene are associated with the risk of hepatitis B virus-related liver diseases in a Chinese population. , 2015, Gene.

[31]  J. Gustafsson,et al.  Comparative proteomic study reveals 17β-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease , 2014, Proceedings of the National Academy of Sciences.

[32]  Y. Xin,et al.  Lack of association between apolipoprotein C3 gene polymorphisms and risk of nonalcoholic fatty liver disease in a Chinese Han population. , 2014, World journal of gastroenterology.

[33]  S. Friedman,et al.  Hepatic stellate cells and liver fibrosis. , 2013, Comprehensive Physiology.

[34]  Z. Kutalik,et al.  Comparative genetic analyses point to HCP5 as susceptibility locus for HCV-associated hepatocellular carcinoma. , 2013, Journal of hepatology.

[35]  J. Hirschhorn,et al.  Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis based on data from the third National Health and Nutrition Examination Survey. , 2013, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[36]  N. Chalasani,et al.  Annals of the New York Academy of Sciences Nonalcoholic Fatty Liver Disease: an Emerging Threat to Obese and Diabetic Individuals , 2022 .

[37]  F. Negro,et al.  Nonalcoholic Fatty Liver Disease in Lean Individuals in the United States , 2012, Medicine.

[38]  Yusuke Nakamura,et al.  Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma , 2011, Nature Genetics.

[39]  O. Cummings,et al.  Design and validation of a histological scoring system for nonalcoholic fatty liver disease , 2005, Hepatology.

[40]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.