Analysis of TM6SF2, PNPLA3, and ATG16L1 Genetic Variants in MASLD and MASH: An Egyptian Case-control Study

Background Metabolic dysfunction associated steatotic liver disease (MASLD) and metabolic dysfunction associated steatohepatitis (MASH), represent complex metabolic liver diseases and a rapidly growing public health burden, particularly in Egypt. Genetic susceptibility plays a pivotal role in modulating disease progression. Variants in Patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2) and Autophagy Related 16-Like 1 (ATG16L1) are among the most relevant genetic determinants implicated in hepatic lipid metabolism, autophagy regulation, and hepatocellular injury. The interplay between these genetic variants and metabolic stress regulators is increasingly recognized as central to disease heterogeneity. Aims This case-control study aimed to provide an integrative evaluation of these genetic variants, elucidating their biochemical associations, and mechanistic roles in MASLD and MASH. Methodology: 150 patients with fibroscan-confirmed MASLD, 150 with MASH and 150 healthy controls were genotyped for PNPLA3 (rs738409), TM6SF2 (rs58542926), and ATG16L1 (rs2241880) using real-time TaqMan assays. Genotypic data were correlated with liver injury biomarkers, lipid profiles, and insulin resistance indices. Results TM6SF2 (rs58542926) TT and CT genotypes, as well as PNPLA3 (rs738409) CG genotype were strongly associated with exacerbated hepatic steatosis and elevated biochemical markers of liver injury. The G allele of ATG16L1 demonstrated modulatory effects on autophagy-related inflammatory pathways. PNPLA3 and ATG16L1 exert complementary and additive effects on hepatic fat accumulation and metabolic derangements. Conclusions The investigated genetic variants showed exhibited biochemical signatures influencing hepatic fat accumulation, autophagy activity, inflammatory response, and fibrosis progression among Egyptian patients. Functional insights were integrated to illuminate how these variants shape disease pathophysiology. Clinical trial registration Not applicable.