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Background and Aim  Non-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated  PNPLA3  rs738409 G-allele on NAFLD-related metabolic traits in hyperglycaemic individuals.    Methods  The rs738409 variant was genotyped in the population-based Inter99 cohort examined by an oral glucose-tolerance test, and a combined study-sample consisting of 192 twins (96 twin pairs) and a sub-set of the Inter99 population ( n  = 63) examined by a hyperinsulinemic euglycemic clamp ( n   total  = 255). In Inter99, we analyzed associations of rs738409 with components of the WHO-defined metabolic syndrome ( n  = 5,847) and traits related to metabolic disease ( n  = 5,663). In the combined study sample we elucidated whether the rs738409 G-allele altered hepatic or peripheral insulin sensitivity. Study populations were divided into individuals with normal glucose-tolerance (NGT) and with impaired glucose regulation (IGR).    Results  The case-control study showed no associations with components of the metabolic syndrome or the metabolic syndrome. Among 1,357 IGR individuals, the rs738409 G-allele associated with decreased fasting serum triglyceride levels (per allele effect(β) = −9.9% [−14.4%;−4.0% (95% CI)],  p  = 5.1×10 −5 ) and fasting total cholesterol (β = −0.2 mmol/l [−0.3;−0.01 mmol/l(95% CI)],  p  = 1.5×10 −4 ). Meta-analyses showed no impact on hepatic or peripheral insulin resistance in carriers of the rs738409 G-allele.    Conclusion  Our findings suggest that the G-allele of  PNPLA3  rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.

The PNPLA3 rs738409 G-Allele Associates with Reduced Fasting Serum Triglyceride and Serum Cholesterol in Danes with Impaired Glucose Regulation