Genetic determinants of hepatocellular carcinoma: role of PNPLA3, FABP2, FADS1/FADS2 genes in Yakuts

BACKGROUND: Hepatocellular carcinoma is an aggressive primary liver cancer. Major risk factors include cirrhosis, hepatitis B and C infections, nonalcoholic fatty liver disease, and type 2 diabetes mellitus. According to state medical statistics of the Russian Federation for 2021, the highest incidence of malignant neoplasms of the liver and intrahepatic bile ducts was reported in the Republic of Sakha (Yakutia). This may be related to dietary changes that have increased the prevalence of obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. AIM: The work aimed to investigate the variability of the PNPLA3, FABP2, FADS1, and FADS2 genes, which are involved in lipid metabolism and associated with nonalcoholic fatty liver disease—a risk factor for hepatocellular carcinoma—in the Yakut population. METHODS: A total of 498 volunteers participated in the study, of whom 126 were diagnosed with nonalcoholic fatty liver disease with concomitant type 2 diabetes mellitus. Single-nucleotide polymorphisms were determined using polymerase chain reaction followed by restriction fragment length polymorphism analysis. RESULTS: In the examined polymorphisms of the PNPLA3, FADS1, and FADS2 genes, a predominance of alleles pathogenic with respect to nonalcoholic fatty liver disease was found in both groups. For the rs1799883 polymorphism of the FABP2 gene, a significant association of the Ala allele with nonalcoholic fatty liver disease and concomitant type 2 diabetes mellitus was identified (p = 0.02). Compared with other populations from the 1000 Genomes project database, a high frequency of alleles pathogenic with respect to nonalcoholic fatty liver disease was observed in the Yakut population. CONCLUSION: The high prevalence of PNPLA3, FABP2, FADS1, and FADS2 gene variants associated with increased body mass index and nonalcoholic fatty liver disease is likely related to an adaptive mechanism for fat accumulation in the liver. With the dietary shift from lipid-protein to predominantly carbohydrate intake, these previously advantageous allelic variants now contribute to metabolic disorders that influence the incidence of liver diseases, including hepatocellular carcinoma.