Additive effects of PNPLA3 and TM6SF2 on the histological severity of non-alcoholic fatty liver disease

Abstract

Introduction: Recent genome-wide association studies have identified that variants in PNPLA3 and TM6SF2 are significantly associated with nonalcoholic fatty liver disease (NAFLD) in multiple ethnic groups. However, the data on their genetic impact on NAFLD in Asian populations are limited. Therefore, we investigated the effects of PNPLA3 rs738409 and TM6SF2 rs58542926 variants on metabolic phenotypes and their combined effects on the histological severity of NAFLD. Methods: In a biopsy-proven NAFLD cohort of 525 subjects, PNPLA3 rs738409 and TM6SF2 rs58542926 were genotyped. Homeostasis model assessment of insulin resistance (HOMA-IR) and adipose tissue insulin resistance (adipo-IR) were calculated. Results: The rs738409 and rs58542926 variants were associated with not only non-alcoholic steatohepatitis (NASH) (odds ratio [OR], 2.00

95% confidence interval [CI], 1.46–2.73 and OR, 1.91

95% CI, 1.04–3.51) but also with significant fibrosis (≥F2) (odds ratio [OR], 1.53

95% CI, 1.11–2.11 and OR, 1.88

95% CI, 1.02–3.46), even after adjustment for metabolic factors. Of both variants, only rs738409 was associated with HOMA-IR and adipo-IR even in healthy controls (P = 0.046 and 0.002, respectively) as well as in the entire study cohort (P = 0.016 and 0.048, respectively). PNPLA3 and TM6SF2 risk variants additively increased the risk of NASH and significant fibrosis (OR per risk allele, 2.03

95% CI, 1.50–2.73 and 1.61

95% CI, 1.19–2.17). Even in subjects with low insulin resistance, the risk of NASH and significant fibrosis increased as the number of risk alleles increased (P = 0.008 and 0.020, respectively). Conclusions: PNPLA3 and TM6SF2 determine the risk of NASH and significant fibrosis, even after adjustment for insulin resistance, and exert an additive effect on NASH and significant fibrosis.