Genetic variants in GCKR and PNPLA3 confer susceptibility to nonalcoholic fatty liver disease in obese individuals.
BACKGROUND
A genome-wide association study identified variants in or near patatin-like phospholipase domain-containing-3 (PNPLA3), neurocan (NCAN), lysophospholipase-like 1 (LYPLAL1), glucokinase regulatory protein (GCKR), and protein phosphatase 1 regulatory subunit 3b (PPP1R3B) that were strongly associated with nonalcoholic fatty liver disease (NAFLD) in adults of European ancestry.


OBJECTIVE
We examined these genetic variants in obese children and tested whether their effects on NAFLD are significant in the Taiwanese Han Chinese population.


METHODS
We genotyped PNPLA3 rs738409, NCAN rs2228603, LYPLAL1 rs12137855, GCKR rs780094, and PPP1R3B rs4240624 in 797 obese children aged 7-18 y. NAFLD was identified by liver ultrasonography. We analyzed the effect of these genetic variants on NAFLD.


RESULTS
NAFLD was identified in 24% of the recruited obese children. We found significant associations with NAFLD at variants in PNPLA3 and GCKR but not in NCAN, LYPLAL1, and PPP1R3B. Multiple logistic regression analysis showed that, after control for the effects of age- and sex-adjusted body mass index, waist-to-hip ratio, sex, and PNPLA3 rs738409 polymorphism, the variant GCKR rs780094 TT genotype independently increased the OR of NAFLD by 1.997 (95% CI: 1.196, 3.335; P = 0.008) compared with the CC genotype. Subjects with the variant GCKR rs780094 TT genotype had a higher mean serum alanine aminotransferase concentration than did those with the CC genotype (30.8 ± 34.7 compared with 22.2 ± 18.6 IU/L; P = 0.01).


CONCLUSIONS
By studying the genetic variants of obese Taiwanese children, we confirmed that the genetic variants in GCKR rs780094 and PNPLA3 rs738409, but not in NCAN rs2228603, LYPLAL1 rs12137855, and PPP1R3B rs4240624, are associated with an increased risk of NAFLD. GCKR and PNPLA3 variants are the common genetic factors that may confer susceptibility to NAFLD in obese individuals across multiple ethnic groups.
Department of Pediatrics, Far Eastern Memorial Hospital, Taipei, Taiwan (Y-CL and P-FC); the Departments of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan (M-HC and Y-HN); and the Oriental Institute of Technology, New Taipei City, Taiwan (Y-CL).
Yu-Cheng
YC
Lin
Pi-Feng
PF
Chang
Mei-Hwei
MH
Chang
Yen-Hsuan
YH
Ni
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000483:Alleles; D044466:Asian People; D015992:Body Mass Index; D002648:Child; D005234:Fatty Liver / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007333:Insulin Resistance; D015810:Linkage Disequilibrium; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000000981:diagnostic imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000503:physiopathology*; D020641:Polymorphism, Single Nucleotide; D013624:Taiwan; D014463:Ultrasonography; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
D048868:Adaptor Proteins, Signal Transducing; D008049:Lipase; D008565:Membrane Proteins; C485100:GCKR protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent