Abstract
ABSTRACT
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
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.