Genetic and non-genetic drivers of histological progression and regression in MASLD

The association between genetic variants and longitudinal changes in liver histology has not been well characterized. We examined relationships between three single nucleotide polymorphisms (SNPs) - PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs72613567 - and longitudinal changes in liver histology.

A total of 671 (444 adults and 227 children) individuals enrolled in different NASH CRN studies and randomized controlled trials, with ≥2 serial liver biopsies, were analyzed. The main outcomes were progression from metabolic dysfunction-associated steatotic liver (MASL) to steatohepatitis (MASH), ≥1 stage increase in fibrosis, and resolution of MASH or fibrosis regression ≥1 stage. Interval-censored Cox models, adjusted for race/ethnicity, sex, age, BMI, type 2 diabetes mellitus (T2DM), and study cluster, were used to examine the associations between genetic variants and histological outcomes.

The PNPLA3 G allele increased the risk of fibrosis progression (adjusted hazard ratio [aHR] 1.31, 95% CI 1.05-1.64). The HSD17B13 A allele attenuated MASL to MASH progression (aHR 0.46, 95% CI 1.5-3.9) and fibrosis progression (aHR 0.69, 95% CI 0.51-0.92) while increasing the likelihood of MASH resolution (aHR 1.58, 95% CI 1.13-2.22) and fibrosis regression (aHR 1.42, 95% CI 1.09-1.85). The TM6SF2 T allele did not influence histological changes. An unweighted 3-SNP polygenic risk score, incorporating PNPLA3, HSD17B13, and TM6SF2 risk alleles, was associated with an increased risk of MASL to MASH progression (aHR 1.33, 95% CI 1.03-1.71) and fibrosis progression (aHR 1.37, 95% CI 1.18-1.60). The unweighted sum of the 3-SNP non-risk alleles was associated with a higher chance of MASH resolution (aHR 1.21, 95% CI 1.02-1.43). Non-genetic factors, including T2DM and BMI change, also independently influenced histology. The effects of single variants and the PRS were significantly modified by age, sex, BMI, and T2DM.

Genetic predisposition and its significant interactions with non-genetic factors drive the dynamic trajectory of MASLD, providing a critical framework for personalized risk stratification and management.

Histological changes in metabolic dysfunction-associated steatotic liver disease are driven by complex interactions between genetic and non-genetic factors, not by isolated influences. The PNPLA3 rs738409 allele worsened fibrosis and steatosis, while the HSD17B13 rs72613567 allele acted as a protective factor against progression and promoted regression. A polygenic risk score (PRS), based on three single nucleotide polymorphisms, comprising the sum of the three risk alleles, independently predicted histological progression. Conversely, the PRS of the three non-risk alleles was associated with histological regression. Non-genetic factors such as age, sex, BMI changes, and type 2 diabetes mellitus significantly modified the impact of both single genetic variants and the PRS on histology. These findings underscore the necessity of considering these multifaceted interactions for personalized MASLD management, including risk stratification and future therapeutic development.