Frequency of the PNPLA3 rs738409 polymorphism and other genetic loci for liver disease in a Guatemalan adult population

Background & Aims: Individuals of Latino ancestry experience disproportionate rates of nonalcoholic fatty liver disease (NAFLD) and other liver disorders. Common genetic variants have been linked to NAFLD, but their prevalence in Guatemalan adults has not been previously examined. Methods: Selected genetic variants including rs738409 (PNPLA3), rs2228603 (NCAN), rs780094 (GCKR), and rs12137855 (LYPLAL1) were examined in a cross-sectional study of 403 adults with low or no alcohol consumption and without viral hepatitis. The primary liver disease measure was an elevated level of aminotransferases (ALT or AST). Regression analyses used additive genetic models and controlled for age, sex, alcohol consumption, ancestry informative markers, and body mass index. For genetic variants with significant associations, we calculated the attributable fraction of elevated ALT/AST. Results: The overall frequency of the PNPLA3 G allele of rs738409 was 0.69. The frequency was higher among persons who self-identified as indigenous compared to persons who did not (0.77 vs. 0.59). The PNPLA3 G allele of rs738409 was significantly associated with elevated ALT/AST (adjusted OR = 2.04, 95% CI 1.38, 3.03). NCAN, GCKR, and LYPLAL1 variants were not associated with the liver disease measures. The estimated attributable fraction of elevated ALT/AST due to the PNPLA3 rs738409 G allele was 33%. Conclusions: There is an exceptionally high prevalence of the PNPLA3 rs738409 risk variant among Guatemalan adults. Future studies are needed to examine the role of genetic testing to inform prevention and management of persons at risk of, or with, NAFLD, and to understand whether environmental factors modulate genetic predisposition.