Inherited risk predicts increases in fibrosis in MASLD patients

Genetic risk score (GRS), polygenic risk score-hepatic fat content (PRS-HFC), its adjusted version (PRS-5), and PNPLA3 genotypes alone show a significant relationship with increased fibrosis severity per decade in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), reports a study.

A total of 570 adults with MASLD (median age 57 years, 56.8 percent women, 34.2 percent Hispanic) were included in this cross-sectional study. Participants underwent magnetic resonance elastography (MRE) and genotyping for PNPLA3, TM6SF2, MBOAT7, GCKR, and HSD17B13.

The researchers calculated GRS as the sum of established risk alleles in PNPLA3 minus protective variants in HSD17B13 (0=low risk, 1=high risk). They also estimated the PRS-HFC and PRS-5. Age-related change in liver stiffness measurement (LSM) on MRS by GRS was the primary endpoint. An external cohort from Latin America was used to validate the findings.

The median MRE was 2.4 kPa among participants, of whom 51 percent had a high GRS. LSM rose for every 10-year age increase (β, 0.28 kPa, 95 percent confidence interval [CI], 0.12–0.44; p=0.001) in the high GRS group, but no such difference was seen in the low GRS group.

The use of PRS-HFC and PRS-5 also yielded similar findings.

Moreover, PNPLA3 genotype was predictive of higher LSM (C/G: β, 0.32 kPa, 95 percent CI, 0.02–0.61; p=0.034; G/G: β, 0.87 kPa, 95 percent CI, 0.52–1.22; p<0.0001), while the G/G genotype correlated with a significantly increased LSM by age 44 years. These findings persisted in the validation population.

“Assessing genetic risk in MASLD will identify high-risk patients who require more frequent monitoring,” the researchers said.