Association of PNPLA3 with non-alcoholic fatty liver disease in a minority cohort: the Insulin Resistance Atherosclerosis Family Study

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Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition, particularly among Hispanic Americans. A genetic variant in PNPLA3 (rs738409) has been identified as a strong predictor of hepatic fat content. To confirm the association of this variant with NAFLD in two minority cohorts, Hispanic Americans and African Americans, in whom liver density was quantified by computed tomography (CT). This analysis was conducted in the Insulin Resistance Atherosclerosis (IRAS) Family Study. Participants were recruited from the general community and included 843 Hispanic American and 371 African American adults aged 18-81 years. A single variant in PNPLA3 (rs738409) was genotyped. Liver density was calculated in Hounsfield Units from abdominal CT scans. Single nucleotide polymorphism (SNP) rs738409 was strongly associated with reduced liver density (i.e. NAFLD) in Hispanic Americans (1.18 × 10⁻⁹) and in African Americans (P=4.99 × 10⁻⁶). The association followed an additive genetic model with the G allele conferring risk. The allele was two times more common in Hispanic Americans than in African Americans (40 vs 19%), consistent with the greater prevalence of NAFLD in Hispanic Americans (24 vs 9%). The SNP explained 4.4 and 5.6% of the variance of the adjusted liver density outcome in Hispanic Americans and African Americans, respectively. We confirmed the association of a PNPLA3 variant with NAFLD in Hispanic Americans and African Americans, suggesting that PNPLA3 contributes to the variation in NAFLD across multiple ethnicities. This study adds to the growing evidence that some of the ethnic variation in NAFLD is genetic.