Association of adiponectin in patatin-like phospholipase domain-containing 3 (PNPLA3) associated hepatic steatosis.

Abstract

184 Background: The I148M polymorphism (rs738409) of the patatin-like phospholipase domain-containing 3 (PNPLA3) gene is strongly associated with hepatic triglyceride content (HTGC) and the development of nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), which are themselves risk factors for hepatocellular cancer (HCC). Serum adiponectin affects insulin resistance and carcinogenesis and has also been associated with HTGC. Whether these risk factors are additive in predisposing to HTGC is unknown. We evaluated the impact of adiponectin and PNPLA3 genotypes on HTGC in a large community cohort. Methods: The Dallas Heart Study (DHS) is a multi-ethnic population based study of Dallas County residents. HTGC was quantified using H-MR spectroscopy. Univariate and multivariable logistic and linear regression models were generated to test the association between HTGC and log adiponectin stratified by PNPLA3 genotype (CC, CG and GG). Models were adjusted for age, gender, race, hypertension, diabetes, HOMA-IR and BMI. Results: There were 2,259 patients who had complete clinical, biochemical, imaging, and genotyping data and were included in this analysis. Median age was 44 and 47% were male. Race distribution was 48% Black, 32% White, and 18% Hispanic. The prevalences of PNPLA3 genotypes were 61% CC (wild type), 32% GC and 7% GG. The median concentration of adiponectin was 6.6 ug/ml. Adiponectin was an independent predictor HTCG across all genotypes after adjusting for covariates (CC b=-0.34, GC b=-0.42, GG b=-0.38, p<0.005 for each). HTGC decreased across gender and race-stratified quartiles of adiponectin for each PNPLA3 genotype, and the qualitative effect was greatest in the I148M homozygotes (table). Conclusions: Adiponectin is independently associated with hepatic steatosis across all three PNPLA3 genotypes. The combination of at-risk PNPLA3 genotypes and hypoadiponectemia is associated with a high risk of hepatic steatosis. Future studies will need to address downstream HCC risk and whether manipulation of adiponectin level may be of clinical benefit. [Table: see text]