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 genome-wide association studies have reported an association between single-nucleotide polymorphism rs738409 in the (patatin-like phospholipase domain-containing protein 3) PNPLA3 gene and FLD. Liver attenuation (LA; 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 LA value of ≤40 HU indicates moderate-to-severe hepatic steatosis.OBJECTIVE: We investigated whether missense rs738409 PNPLA3 interacted with abdominal visceral adipose tissue (VAT) volume (cm 3) to reduce LA (that is, increased liver fat) in 1019 European American men and 1238 European American women from the Family Heart Study.METHODS:We used linear regression to test the additive effect of genotype, abdominal VAT, and their multiplicative interaction on LA adjusted for age, body mass index, high-density lipoprotein-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 (minor allele frequency 0.23) and 100 cm 3 /150 mm slice VAT decreased LA by 2.68±0.35 HU (P<0.01). The interaction of 100 cm 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 with men. The presence of the PNPLA3 variant genotype, particularly in the context of high VAT content may have an important role in FLD.