Egyptian MASLD genetic map; between the leading TM6SF2 gene and role of epigenetic

Metabolic dysfunction-associated steatotic liver disease (MASLD) is influenced by genetic variants, but population-specific data from Egypt are limited. This study investigated GCKR (rs1260326), PNPLA3 (rs738409), and TM6SF2 (rs58542926) variants impact on MASLD severity and their association with cardiometabolic risk factors in an Egyptian cohort. This prospective case–control study included 476 adults (244 MASLD patients, 232 healthy controls). All participants underwent anthropometric assessment, liver ultrasound, and vibration-controlled transient elastography (VCTE) with controlled attenuation parameter (CAP) to quantify steatosis and fibrosis. Laboratory analysis included lipid profile, liver enzymes, fasting glucose, insulin, HbA1c, and HOMA-IR. Genotyping was performed using real-time PCR. TM6SF2 T variant allele was the strongest predictor of MASLD (16% vs. 9% in controls, p < 0.001), associated with higher CAP (P = 0.03) and elevated liver enzymes. PNPLA3showed no association with MASLD (24% allele frequency in both groups). Unexpectedly, GCKR wild-type C allele was associated with higher insulin levels and HOMA-IR. Haplotype analysis revealed a synergistic effect between GCKR wild-type C allele and TM6SF2 variant T allele, conferring a 2.81-fold increased MASLD risk (95% CI: 1.63–4.84). HDL < 40 mg/dL (OR = 2.7), BMI, and HOMA-IR were the strongest independent predictors. None of the variants significantly impacted fibrosis severity. The Egyptian MASLD genetic landscape features a dominant role for TM6SF2, a negligible role for PNPLA3, and paradoxical GCKR wild-type associations, implicating epigenetic factors or nutrigenomic interactions likely reflecting Egypt’s unique nutritional transition and high consanguinity rates and that may modulate the expression and phenotypic penetrance of these established genetic variants.