Background & Aims: Metabolic dysfunction associated steatotic liver disease (MASLD) has a strong genetic component. The aim of this study was to examine noninvasively the prevalence of MASLD and of advanced fibrosis in relatives of patients with advanced MASLD and the risk factors for liver involvement, with a focus on the contribution of common genetic risk variants. Methods: We prospectively enrolled 98 consecutive probands with advanced fibrosis and/or hepatocellular carcinoma caused by MASLD and 160 nontwin first-degree relatives noninvasively screened for MASLD and advanced fibrosis at 4 Italian centers. We evaluated common genetic determinants and polygenic risk scores of liver disease. Results: Among relatives, prevalence of MASLD was 56.8% overall, whereas advanced fibrosis was observed in 14.4%. At multivariable analysis in relatives, MASLD was associated with body mass index (odds ratio [OR], 1.31 [1.18–1.46]) and tended to be associated with diabetes (OR, 5.21 [0.97–28.10]), alcohol intake (OR, 1.32 [0.98–1.78]), and with female sex (OR, 0.54 [0.23–1.15]), whereas advanced fibrosis was associated with diabetes (OR, 3.13 [1.16–8.45]) and nearly with body mass index (OR, 1.09 [1.00–1.19]). Despite that the PNPLA3 risk variant was enriched in probands (P =.003) and overtransmitted to relatives with MASLD (P =.045), evaluation of genetic risk variants and polygenic risk scores was not useful to guide noninvasive screening of advanced fibrosis in relatives. Conclusions: We confirmed that about 1 in 7 relatives of patients with advanced MASLD has advanced fibrosis, supporting clinical recommendations to perform family screening in this setting. Genetic risk variants contributed to liver disease within families but did not meaningfully improve fibrosis risk stratification.
