title: Interactions of a PPARGC1A Variant and a PNPLA3 Variant Affect Nonalcoholic Steatohepatitis in Severely Obese Taiwanese Patients.
abstract: The patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant is associated with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). However, the role of genetic variations of the peroxisome proliferator-activated receptor gamma coactivator-1-alpha gene (PPARGC1A) and glucokinase regulatory (GCKR) gene on NASH in obese patients remains unclear. We studied the effects and interaction of these genetic polymorphisms on NASH in severely obese Taiwanese patients.The genotypes of PPARGC1A rs8192678, PNPLA3 rs738409, and GCKR rs780094 were determined in 177 severely obese patients who underwent bariatric surgery. NASH was evaluated by liver histopathology.Of 177 patients, 29 (16.4%), 57 (33.2%), and 91 (51.4%) were in the non-NAFLD, steatosis, and NASH groups, respectively. We found that the PPARGC1A and PNPLA3 variants, but not the GCKR variant, were associated with NASH. The PPARGC1A rs8192678 GA/AA genotype was associated with higher steatosis grade and presence of ballooning degeneration. The PNPLA3 rs738409 GG genotype was associated with higher severity in all histologic features except for fibrosis. In multivariate analysis, both the PPARGC1A rs8192678 GA/AA genotype (odds ratio [OR] 2.32; 95% confidence interval [CI] 1.08-4.98; P = 0.031) and the PNPLA3 rs738409 GG genotype (OR 4.05; 95% CI 1.24-13.23; P = 0.021), and also body mass index were independent risk factors for NASH. Further, there was an additive effect of the PPARGC1A rs8192678 GA/AA genotype and the PNPLA3 rs738409 GG genotype on the presence of NASH (OR 6.83; 95% CI 1.61-29.01; P = 0.009).The PPARGC1A rs8192678 GA/AA genotype and the PNPLA3 rs738409 GG genotype had an additive effect on NASH in severely obese Taiwanese patients.
authors.affiliation: From the Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University (C-MT, C-FH, J-FH, C-YD, W-LC, M-LY); Department of Internal Medicine (C-MT); Department of Bariatric and Metabolic International Surgery Center, E-Da Hospital, I-Shou University (C-MT, C-KH); Department of Public Health and Environmental Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung (H-PT); Department of Pathology, Lin Shin Hospital, Taichung (J-CH); Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung (M-LY, C-FH, J-FH, C-YD, W-LC, M-LY); Faculty of Internal Medicine, School of Medicine, College of Medicine, and Lipid Science and Aging Research Center, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University (M-LY); and Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan (M-LY).
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Tai
authors.forename: Chih-Kun
authors.initials: CK
authors.lastname: Huang
authors.forename: Hung-Pin
authors.initials: HP
authors.lastname: Tu
authors.forename: Jau-Chung
authors.initials: JC
authors.lastname: Hwang
authors.forename: Ming-Lun
authors.initials: ML
authors.lastname: Yeh
authors.forename: Chung-Feng
authors.initials: CF
authors.lastname: Huang
authors.forename: Jee-Fu
authors.initials: JF
authors.lastname: Huang
authors.forename: Chia-Yen
authors.initials: CY
authors.lastname: Dai
authors.forename: Wan-Long
authors.initials: WL
authors.lastname: Chuang
authors.forename: Ming-Lung
authors.initials: ML
authors.lastname: Yu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000483:Alleles; D050110:Bariatric Surgery; D001706:Biopsy; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000473:pathology; D009767:Obesity, Morbid / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011110:Polymorphism, Genetic / Q000235:genetics*; D013624:Taiwan; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008049:Lipase; D008565:Membrane Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; C485100:GCKR protein, human; C486497:PPARGC1A protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent