Abstract / Summary
Background: Metabolic dysfunction-associated steatotic disease (MASLD) affects increasing numbers of patients worldwide. The PNPLA3 p.I148M variant represents a major genetic determinant of MASLD progression. The loss-of-function HSD17B13 polymorphism rs72613567 was reported in turn to be hepatoprotective.
Patients: We analysed blood samples of 507 patients recruited within the Fatty Liver Assessment in Germany (FLAG) study, of whom 476 (255 males, age 56 years) were genotyped. FLAG is a multicenter real-world MASLD cohort covering secondary and tertiary healthcare levels. The PNPLA3 p.I148M and the HSD17B13 rs72613567 polymorphisms were genotyped using allelic discrimination assays. The control cohort comprised 174 individuals.
Results: The PNPLA3 p.I148M variant was prevalent among FLAG patients (p < 0.001 for the departure from Hardy-Weinberg equilibrium) and increased the risk of developing MASLD (common OR = 2.46, p = 6.238e-09). It was associated with increased ALT and AST, lower serum triglyceride concentrations, and independently with liver stiffness ≥ 9.1 kPa after adjustment for BMI and diabetes (OR = 2.57, p = 0.01). Carriers of the HSD17B13 rs72613567 variant had lower AST. HSD17B13 heterozygotes had lower FIB-4 (p = 0.028) and lower liver stiffness (p = 0.034). Among carriers of the PNPLA3 p.148M allele, the presence of the HSD17B13 variant was associated with lower ALT (p = 0.023) and AST (p = 0.041); however, HSD17B13 did not abrogate the association of PNPLA3 with liver fibrosis (adjusted p = 0.013).
Discussion: By analysing a real-world MASLD cohort in Germany, we further underscore the role of the PNPLA3 variant as the central genetic trigger and modulator of MASLD. The HSD17B13 polymorphism may exert protective effects in MASLD and could attenuate some PNPLA3-associated effects.