Abstract
Introduction: Metabolic dysfunction associated steatotic liver disease (MASLD), previously termed as nonalcoholic fatty liver disease (NAFLD), is a growing global health concern, particularly in South Asia. While PNPLA3 is a well-recognized genetic contributor to MASLD, the role of other metabolic genes, such as ABCC8, remains unexplored in South Asian populations. In this study, we aim to investigate the genetic association and potential synergy between PNPLA3 (rs738409) and ABCC8 (rs146378237) variants in MASLD pathogenesis in a Pakistani cohort. Methods: A two-phased case-control study was conducted. Whole Exome Sequencing (WES) was performed on 6 MASLD cases and 6 healthy controls to identify relevant variants, followed by validation via Sanger sequencing in an extended MASLD cohort (n = 52). Variant frequencies were compared with 96 ethnically matched controls from the 1000 Genomes Project. Furthermore, the association of the variants with clinical, biochemical, and fibrotic parameters was assessed. Results: The PNPLA3 rs738409 G allele (MAF = 0.47) and ABCC8 rs146378237 T allele (MAF = 0.36) were significantly enriched in MASLD cases and strongly associated with cirrhosis. The TT genotype of ABCC8 was also linked to T2DM and low HDL levels. Importantly, eight MASLD patients harbored both GG (PNPLA3) and TT (ABCC8) genotype, and all were known cases of diabetes, suggesting a synergistic genetic interaction. Conclusions: This is the first report of ABCC8 rs146378237 in a South Asian MASLD cohort, revealing population-specific risk and a gene-gene interaction that may inform targeted screening and personalized management of MASLD in high-risk diabetic individuals.