A PNPLA3 polymorphism confers lower susceptibility to incident diabetes mellitus in subjects with nonalcoholic fatty liver disease.

Abstract Background and aims We investigated the association between the patatin-like phospholipase domain-containing-3 (PNPLA3) rs738409 genotype and the risk of diabetes mellitus (DM) using a biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) cohort and a longitudinal observational cohort. Methods Associations between genotypes and the prevalence of DM were evaluated with stratification according to the histological severity of NAFLD in the Boramae cohort (n = 706). A longitudinal cohort consisting of non-diabetic individuals with ≥2 health check-ups was then selected to investigate the risk of incident DM according to the genotype (the GENIE cohort; n = 4,998). Results Among subjects with NAFLD in the Boramae cohort, the G allele was independently associated with a lower prevalence of DM in both nonalcoholic fatty liver (odds ratio [OR] per 1 allele, 0.66; 95% confidence interval [CI], 0.46–0.97) and nonalcoholic steatohepatitis (OR per 1 allele, 0.59; 95% CI, 0.38–0.92). This result was replicated in the longitudinal GENIE cohort. The G allele was associated with a lower risk of incident DM during the median follow-up of 60 months in subjects with NAFLD (hazard ratio, 0.65; 95% CI, 0.45–0.93). In contrast, G allele-carriers without NAFLD showed higher odds for DM in the context of the Boramae cohort (OR, 2.44; 95% CI, 1.00–5.95). Conclusions These findings clarify conflicting results regarding the association between the PNPLA3 rs738409 genotype and the risk of DM, demonstrating a clear difference between subjects with and without NAFLD; this difference might be explained by the low metabolic risk in genetic NAFLD.