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

The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
PLoS ONE (Impact Factor: 3.23). 07/2012; 7(7):e40376. DOI: 10.1371/journal.pone.0040376
Source: PubMed


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.
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).
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.
Our findings suggest that the G-allele of PNPLA3 rs738409 associates with reduced fasting levels of cholesterol and triglyceride in individuals with IGR.

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    • "The strongest genetic risk factor for NAFLD is by far the I148M variant of patatin-like phospholipase domaincontaining 3 (PNPLA3; encoded by rs738409 C[G singlenucleotide polymorphism). The I148M variant influences liver fat without independently of body mass index, dyslipidemia , or insulin resistance, and it has been associated with severe steatosis, NASH, and liver fibrosis (Valenti et al. 2002, 2006, 2010a, b; Miele et al. 2008; Dongiovanni et al. 2010), even if severe obesity exposed an association between I148M, insulin resistance, and lower triglycerides in Northern European subjects (Krarup et al. 2012; Palmer et al. 2012). We previously showed that in overweight children with increased liver enzymes, the PNPLA3 I148M polymorphism is enriched compared to the general population (homozygosity for the 148M risk allele was 16 vs. 5 % in the general population) and represents a non-invasive early marker of NASH and fibrosis (Valenti et al. 2010a). "
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