Abstract 20253: Insulin Resistance Traits but Not Cardiometabolic Dyslipidemia Interact With PNPLA3-rs738409 G-allele to Exacerbate Nonalcoholic Fatty Liver Disease
Non-alcoholic fatty liver disease (NAFLD) is a complex disease caused by an excessive deposition of fat in the liver. NAFLD is correlated with the presence of related metabolic diseases including obesity, diabetes, and dyslipidemia which are risk factors for cardiovascular disease. We previously demonstrated that the PNPLA3-rs738409 G-allele (I148M) promotes fatty liver across multiple ancestries. How this variant interacts with metabolic traits to influence fatty liver, however, has not been well defined. The goal of this study was to identify metabolic traits that exacerbate fat deposition in the presence of the PNPLA3-rs738409 G-allele in an effort to find ways to mitigate genetic risk.
We tested whether liver fat, measured non-invasively with computed tomography, is modulated by the interaction of PNPLA3-rs738409 with metabolic factors including insulin resistance (HOMA-IR), insulin and glucose levels, body mass index (BMI), waist-hip-ratio adjusted for BMI (WHRadjBMI), triglycerides, HDL-cholesterol, and LDL-cholesterol. We controlled for sex, age, alcohol consumption and population substructure after excluding diabetics from the HOMA-IR, insulin and glucose models and statin users from the LDL model. Results were meta-analyzed across 7 population studies: FramHS, GENOA, AMISH, AGES, MESA, CARDIA, and FHS. The analyses included up to a total of 14,055 individuals from European (n=11,174) and African ancestry (n=2,881).
We found statistically significant interactions of PNPLA3-rs738409 G-allele (frequency= 0.23) in promoting increased liver fat with increased insulin, HOMA-IR, glucose, BMI, WHRadjBMI and triglycerides after applying a Bonferroni correction for 3 metabolic domains: insulin-glucose, adiposity, and lipids (p<0.0166). However, we did not find significant interactions with LDL-cholesterol or HDL-cholesterol.
In this large population study for NAFLD, we find that the presence of insulin resistance, more than the presence of cardiometabolic disease promoting hyperlipidemia (high LDL/low HDL), exacerbates NAFLD in patients carrying the PNPLA3-rs738409 G-allele and suggests that reducing insulin resistance (e.g. metformin) more than reducing LDL (statins) may reduce NAFLD in these populations.
Author Disclosures: L. Barata: None. M.F. Feitosa: None. L.F. Bielak: None. B. Halligan: None. A. Baldridge: None. J. Yao: None. A.V. Smith: None. G. Kjartan: None. L. Yerges-Armstrong: Employment; Significant; Glaxo SmithKlein. X. Guo: None. L.J. Rasmussen-Torvik: None. J.R. O’Connell: None. P.A. Peyser: None. I. Borecki: Employment; Significant; Regeneron Pharmaceuticals. E.K. Speliotes: None. M. Province: None.
- © 2016 by American Heart Association, Inc.