Association of polymorphisms in GCKR and TRIB1 with nonalcoholic fatty liver disease and metabolic syndrome traits.
In several genome-wide association studies, nonalcoholic fatty liver disease and alanine aminotransferase susceptibility variants have been identified in several genes, including LYPLAL1, ZP4, GCKR, HSD17B13, PALLD, PPP1R3B, FDFT1, TRIB1, COL13A1, CPN1, ERLIN1, CWF19L1, EFCAB4B, PZP, and NCAN. To investigate the relationship between these genes and nonalcoholic fatty liver disease in the Japanese population, we genotyped 540 patients and 1012 control subjects for 18 variations. We performed logistic regression analyses to characterize the association between the tested variations and nonalcoholic fatty liver disease. Metabolic syndrome and histological traits were also analyzed by linear regression. We also examined GCKR rs780094, TRIB1 rs2954021, and PNPLA3 rs738409 for epistatic effects. The A-allele of rs780094 in GCKR (P = 0.0024) and the A-allele of rs2954021 TRIB1 (P = 4.5×10⁻⁵) were significantly associated with nonalcoholic fatty liver disease. GCKR rs780094 was also associated with decreased plasma glucose, and increased triglycerides in the patient and control groups. GCKR rs780094 was also associated with an increased ratio of visceral to subcutaneous fat area in the patients with nonalcoholic fatty liver disease. Variations in GCKR, TRIB1, and PNPLA3 independently influenced nonalcoholic fatty liver disease and had no epistatic effects. Our data suggest variations in GCKR and TRIB1 are involved in the development of nonalcoholic fatty liver disease.
Medical Research Support Center, Pharmacogenomics, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Aya
A
Kitamoto
Takuya
T
Kitamoto
Takahiro
T
Nakamura
Yuji
Y
Ogawa
Masato
M
Yoneda
Hideyuki
H
Hyogo
Hidenori
H
Ochi
Seiho
S
Mizusawa
Takato
T
Ueno
Kazuwa
K
Nakao
Akihiro
A
Sekine
Kazuaki
K
Chayama
Atsushi
A
Nakajima
Kikuko
K
Hotta
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007564:Japan; D008049:Lipase / Q000235:genetics* / Q000378:metabolism; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D024821:Metabolic Syndrome / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008049:Lipase; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; C485100:GCKR protein, human; C493170:TRIB1 protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent