title: Association of diabetes and PNPLA3 genetic variants with disease severity of patients with chronic hepatitis C virus infection.
abstract: OBJECTIVE
  Genetic variants of patatin-like phospholipase domain-containing 3 (PNPLA3) and diabetes are associated with liver disease severity, in patients with chronic hepatitis C (CHC) infection. We aimed at exploring their interaction in determining hepatitis C virus (HCV)-related liver fibrosis.
  
  
  METHODS
  The PNPLA3 genetic polymorphism at rs738409 was verified in 1077 biopsy-proven CHC patients. Other clinical variables, including diabetes status, were analysed for factors associated with bridging fibrosis.
  
  
  RESULTS
  Patients with advanced liver fibrosis had higher proportions of the GG genotype (14.5% vs. 10.4%, p=0.06 in recessive model) and GG/GC genotype carriage (64.0% vs. 56.8%, p=0.03 in dominant model). Stepwise logistic regression analysis revealed that factors predictive of advanced liver fibrosis included age (odds ratio [OR]: 1.02, 95% confidence intervals [CI]: 1.008-1.037, p=0.002), diabetes (OR: 1.81, CI: 1.236-2.653, p=0.002), α-fetoprotein (OR: 1.006, CI: 1.001-1.01, p=0.01), platelet counts (OR: 1.009, CI: 1.006-1.012, p<0.001), and PNPLA3 rs738409 CG/GG genotype (OR: 1.34, CI: 1.006-1.785, p=0.046). When patients were grouped according to their diabetes status, the PNPLA3 genetic variants were associated with advanced liver fibrosis in diabetic patients only, but not in non-diabetic patients. The PNPLA3 gene was the most important predictive factor of bridging fibrosis in diabetic patients, using the recessive model (OR: 4.53, CI: 1.356-15.106, p=0.014) or the dominant model (OR: 2.20, CI: 1.026-4.734, p=0.04). Compared to non-diabetic patients, patients with the diabetes/GG genotype were more likely to have advanced liver fibrosis (OR: 8.79, CI: 2.889-26.719, p<0.001), followed by those with diabetes/non-GG genotype (OR: 1.55, CI: 1.048-2.286, p=0.03).
  
  
  CONCLUSIONS
  The effect of PNPLA3 genetic variants in HCV-related advanced liver fibrosis was enhanced in diabetic patients. The strong genetic-environmental interaction contributed to the high risk of advanced liver disease in CHC patients.
authors.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chung-Feng
authors.initials: CF
authors.lastname: Huang
authors.affiliation: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Chia-Yen
authors.initials: CY
authors.lastname: Dai
authors.affiliation: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ming-Lun
authors.initials: ML
authors.lastname: Yeh
authors.affiliation: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Ching-I
authors.initials: CI
authors.lastname: Huang
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Tai
authors.affiliation: Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Meng-Hsuan
authors.initials: MH
authors.lastname: Hsieh
authors.affiliation: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Liang
authors.affiliation: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ming-Yen
authors.initials: MY
authors.lastname: Hsieh
authors.affiliation: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Hua-Ling
authors.initials: HL
authors.lastname: Yang
authors.affiliation: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Jee-Fu
authors.initials: JF
authors.lastname: Huang
authors.affiliation: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Zu-Yau
authors.initials: ZY
authors.lastname: Lin
authors.affiliation: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shinn-Cherng
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. Electronic address: fish6069@gmail.com.
authors.forename: Ming-Lung
authors.initials: ML
authors.lastname: Yu
authors.affiliation: Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wan-Long
authors.initials: WL
authors.lastname: Chuang
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D048909:Diabetes Complications / Q000235:genetics* / Q000473:pathology; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000150:complications / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008103:Liver Cirrhosis / Q000150:complications / Q000235:genetics / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D012307:Risk Factors; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: CHC; DM; HCV; Liver fibrosis; PNPLA3; SNP