👤 Craig C Teerlink

BACKGROUNDMetabolic dysfunction-associated steatotic liver disease (MASLD) has a substantial inherited component. Rare variants in apolipoprotein B gene (APOB) have been implicated in susceptibility to liver steatosis, but their role in disease progression and outcomes is unclear.METHODSWe investigated APOB rare variants in a case-control cohort of people with advanced MASLD versus healthy controls (n = 510 and 261, respectively), a family-based study (n = 43 and literature meta-analysis), the Million Veteran Program (MVP) cohort (n = 94,885), and the UK Biobank (UKBB) (n = 417,657).RESULTSIn the clinical cohort, APOB variants were enriched in people with advanced MASLD (OR 13.8, 95% CI: 2.7-70.7, P = 0.002) and associated with lower circulating lipids, but higher MASLD activity and fibrosis (P < 0.05). In the family study, APOB variants segregated with hepatic steatosis and fibrosis (P < 0.05). Cross-ancestry meta-analysis of the study cohorts yielded pooled ORs for cirrhosis and hepatocellular carcinoma (HCC) of 1.82, 95% CI: 1.33-2.49 and 3.53, 95% CI: 2.09-5.98, respectively. Variants affecting specifically ApoB100 had a 3-fold greater effect on hepatic lipid metabolism compared with those impairing also ApoB48 and were specifically protective against coronary artery disease (P < 0.05). The variants affected cirrhosis risk similarly, but ApoB48/100 had a larger effect on HCC (P < 0.05).CONCLUSIONSRare APOB variants predispose individuals to advanced MASLD and HCC, with distinct contributions from disrupted VLDL and chylomicrons secretion. These findings highlight the interplay between hepatic and intestinal lipid handling, suggesting that APOB genotyping may enhance MASLD risk stratification and patient identification.FUNDINGEuropean Union, Italian Ministry of Health, Swedish Research Council, Veterans Health Administration, NIH. Show less

Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. Show less

The main genetic factors for familial melanoma remain unknown in >75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high-risk melanoma susceptibility genes explain <3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3, and 6 families with 2, 3, and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1-q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4, and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD >1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family-specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409), and 11q13.3-q21 (max. TLOD 2.654). Future next-generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors. Show less