Clinical Setting Modulates the Association Between Genetic Variants and Fibrosis Severity Across the Spectrum of...

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease worldwide. Although genetic variants are linked to MASLD progression, whether their associations with fibrosis severity are consistent across clinical contexts remains unclear.

A cross-sectional analysis of 6446 individuals with MASLD from a community-based (n = 4477) and a tertiary-care hepatology population (n = 1969) was conducted. Fibrosis severity was assessed using the fibrosis-4 (FIB-4) index. Associations between MASLD-related genetic variants (PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738) and fibrosis were evaluated using multivariable logistic regression within each population.

Advanced fibrosis was more prevalent in the tertiary-care population than in the community-based population (FIB-4 > 1.30: 34.5% vs. 41.2%; FIB-4 ≥ 3.25: 8.4% vs. 0.4%). PNPLA3 rs738409 showed consistent associations with fibrosis severity in both populations, with markedly stronger effects in the tertiary-care setting. In the community-based population, the GG genotype was associated with significant fibrosis (FIB-4 > 1.30; adjusted OR 1.28; 95% CI, 1.03-1.60; P for trend = 0.015), but not with higher thresholds. In contrast, in the tertiary-care population, the GG genotype was strongly associated with FIB-4 > 1.30 (OR 3.11; 95% CI, 2.23-4.34), and FIB-4 ≥ 3.25 (OR 4.17; 95% CI, 2.60-6.67; all P for trend < 0.001). TM6SF2 rs58542926 showed modest associations only in the community-based population, while MBOAT7 rs641738 was not associated with fibrosis severity.

Genetic associations with fibrosis in MASLD appear to be context dependent. PNPLA3 rs738409 shows consistent but markedly greater effect sizes in tertiary-care settings, suggesting that clinical and metabolic context may play an important role in modulating genetic risk beyond ancestry alone.