High inherited risk predicts age-associated increases in fibrosis in patients with MASLD

Abstract

Background & aims: Limited data have prevented routine genetic testing from being integrated into clinical practice in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to quantify the effect of genetic variants on changes in fibrosis severity per decade in patients with MASLD.

Methods: This cross-sectional study included prospectively recruited adults with MASLD aged 18-70 who underwent magnetic resonance elastography (MRE) and genotyping for PNPLA3, TM6SF2, MBOAT7, GCKR, and HSD17B13. A genetic risk score (GRS) was calculated as the sum of established risk alleles in PNPLA3 minus protective variants in HSD17B13 (0 = low risk, 1 = high risk). We also estimated the polygenic risk score-hepatic fat content (PRS-HFC) and the adjusted version (PRS-5). The primary endpoint was the age-related change in liver stiffness measurement (LSM) on MRE by GRS. Findings were validated using an external cohort from Latin America.

Results: Among 570 participants, the median age was 57 [49-64] years, 56.8% were women, and 34.2% were Hispanic. Median MRE was 2.4 [2.1-3.0] kPa, and 51% had a high GRS. In the high GRS group, LSM increased per 10-year age increase (β = 0.28 kPa, 95% CI 0.12-0.44, p = 0.001), while no such difference was observed in the low GRS group. Similar findings were observed using PRS-HFC and PRS-5. PNPLA3 genotype alone also predicted higher LSM (C/G: β = 0.32 kPa, 95% CI 0.02-0.61, p = 0.034; G/G: β = 0.87 kPa, 95% CI 0.52-1.22, p <0.0001) and the G/G genotype was associated with a significantly higher LSM by age 44, which was consistent in the validation population.

Conclusion: GRS, PRS-HFC, PRS-5, and PNPLA3 genotypes alone are associated with increased fibrosis severity per decade, resulting in divergent disease trajectories starting in midlife. Assessing genetic risk in MASLD will identify high-risk patients who require more frequent monitoring.

Impact and implications: This study provides granular evidence that genetic predisposition, particularly the PNPLA3 G/G genotype, significantly influences the trajectory of liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), with a more pronounced impact emerging after the fourth decade of life. These findings highlight the importance of incorporating genetic risk assessment into MASLD management, as it allows for the early identification of high-risk individuals who may benefit from more frequent monitoring and targeted interventions. Given the rising global burden of MASLD, clinicians, researchers, and policymakers should consider integrating genetic stratification into existing risk assessment frameworks to refine screening and surveillance strategies. By optimizing patient selection for non-invasive fibrosis assessment and potential therapeutic interventions, this approach could enhance precision medicine efforts and may improve long-term outcomes.

Keywords: MAFLD; NAFLD; NITs; PNPLA3; cirrhosis; genetic risk score; metabolic dysfunction-associated fatty liver disease; non-alcoholic cirrhosis; non-alcoholic fatty liver disease; noninvasive tests; screening; steatotic liver disease.