Genetic Susceptibility Versus Fibrosis Progression in North Indian Metabolic Dysfunction-Associated Steatotic Liver Disease: Distinct Roles of APOC3 and PNPLA3 in a Candidate Gene Study.

BACKGROUND/AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 30-38% of Indian adults, yet the contribution of genetic risk variants to disease susceptibility and fibrosis progression remains poorly characterised. We investigated 12 candidate single-nucleotide polymorphisms (SNPs) in North Indian patients, benchmarking allele frequencies against IndiGenomes and global populations. METHODS: Sixty-nine patients with MASLD (75.4% male; median body mass index 29.8 kg/m2) from a tertiary care liver clinic in New Delhi were genotyped for 12 SNPs using Illumina custom BeadChip array and Sanger sequencing. Patients were stratified by liver stiffness measurement (LSM): significant fibrosis (≥8 kPa, n = 38) versus no significant fibrosis (<8 kPa, n = 31). Allele frequencies were compared with IndiGenomes (∼1020 Indian individuals) and 1000 Genomes populations. RESULTS: PNPLA3 rs738409G allele was the strongest within-cohort predictor of significant fibrosis (allelic odds ratio [OR] 2.89, 95% confidence interval [CI] 1.35-6.19, P = 0.006; dominant model OR 3.94, P = 0.008), with carriers demonstrating higher LSM (median 15.6 vs 7.5 kPa, P = 0.005). SAMM50 rs3761472 (OR 2.12, P = 0.065) and FTO rs9939609 (OR 2.08, P = 0.089) showed nonsignificant trends. In the population-level comparison, APOC3 rs2854116T allele was the only variant significantly enriched after Bonferroni correction (64.0% vs 47.9%; OR 1.93, 95% CI 1.35-2.77; P < 0.001), followed by PNPLA3 (33.3% vs 24.1%, OR 1.57, P = 0.019) and SAMM50 (31.2% vs 22.6%, OR 1.55, P = 0.028). Notably, APOC3 showed no association with fibrosis (OR 0.96, P = 1.000), suggesting a role in susceptibility rather than progression. CONCLUSION: In this exploratory cohort of North Indian patients with MASLD, we observe a dissociation between genetic determinants of disease susceptibility and fibrosis progression. APOC3 rs2854116 is enriched relative to the Indian population reference, suggesting a potential susceptibility association, while PNPLA3 rs738409 is associated with fibrosis severity within established disease. These hypothesis-generating findings support ancestry-specific approaches to genetic risk stratification in Indian MASLD.