Association of polymorphisms in <i>GCKR</i> and <i>TRIB1</i> 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 <i>LYPLAL1</i>, <i>ZP4</i>, <i>GCKR</i>, <i>HSD17B13</i>, <i>PALLD</i>, <i>PPP1R3B</i>, <i>FDFT1</i>, <i>TRIB1</i>, <i>COL13A1</i>, <i>CPN1</i>, <i>ERLIN1</i>, <i>CWF19L1</i>, <i>EFCAB4B</i>, <i>PZP</i>, and <i>NCAN</i>. 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 <i>GCKR</i> rs780094, <i>TRIB1</i> rs2954021, and <i>PNPLA3</i> rs738409 for epistatic effects. The A-allele of rs780094 in <i>GCKR</i> (<i>P</i> = 0.0024) and the A-allele of rs2954021 <i>TRIB1</i> (<i>P</i> = 4.5×10^-5) were significantly associated with nonalcoholic fatty liver disease. <i>GCKR</i> rs780094 was also associated with decreased plasma glucose, and increased triglycerides in the patient and control groups. <i>GCKR</i> rs780094 was also associated with an increased ratio of visceral to subcutaneous fat area in the patients with nonalcoholic fatty liver disease. Variations in <i>GCKR</i>, <i>TRIB1</i>, and <i>PNPLA3</i> independently influenced nonalcoholic fatty liver disease and had no epistatic effects. Our data suggest variations in <i>GCKR</i> and <i>TRIB1</i> are involved in the development of nonalcoholic fatty liver disease.