PNPLA3 gene-by-visceral adipose tissue volume interaction and the pathogenesis of fatty liver disease: The NHLBI Family Heart Study

BACKGROUND: Fatty liver disease (FLD) is characterized by increased intrahepatic triglyceride content with or without inflammation and is associated with obesity, and features of the metabolic syndrome. Several recent GWAS have reported an association between SNP rs738409 in the PNPLA3 gene and FLD. Liver attenuation (Hounsfield Units, HU) by computed tomography is a non-invasive measure of liver fat, with lower values of HU indicating higher liver fat content. Clinically, a liver attenuation (LA) value of ≤ 40 HU indicates moderate-to-severe hepatic steatosis. OBJECTIVE: We investigated whether missense rs738409 PNPLA3 interacted with abdominal visceral adipose tissue volume (cm(3)) to reduce liver attenuation (i.e. increased liver fat) in 1,019 European American men and 1,238 European American women from the Family Heart Study. METHODS: We used linear regression to test the additive effect of genotype, abdominal visceral adipose tissue (VAT), and their multiplicative interaction on LA adjusted for age, BMI, HDL-cholesterol, insulin resistance, serum triglycerides, abdominal subcutaneous adipose tissue, and alcohol intake. RESULTS: In men and women combined, the interaction between each copy of the rs738409 variant allele (MAF 0.23) and 100cm(3)/150mm slice VAT decreased LA by 2.68±0.35 HU (p < 0.01). The interaction of 100cm(3) VAT and the variant allele was associated with a greater decrease in LA in women than men (−4.8±0.6 and −2.2±0.5 HU, respectively). CONCLUSIONS: The interaction between genotype and VAT volume suggest key differences in the role of PNPLA3 genotype in conjunction with abdominal VAT in liver fat accrual. The stronger association of the PNPLA3 genotype and liver fat in women suggests that women may be more sensitive to liver fat accumulation in the setting of increased visceral fat, compared to men. The presence of the PNPLA3 variant genotype, particularly in the context of high visceral adipose tissue content may play an important role in FLD.