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Growing evidence suggests that cholestatic and fatty liver disease share common pathophysiological mechanisms. Rare loss-of-function variants in the ATP binding cassette subfamily B member 4 (ABCB4) gene have been associated with gallstone disease and with a spectrum of cholestatic liver diseases, ranging from progressive familial intrahepatic cholestasis to less severe conditions, like low phospholipid-associated cholelithiasis or intrahepatic cholestasis during pregnancy. Whole-genome sequencing of Icelanders revealed the common variant rs2109505 T>A in ABCB4 , conferring protection against gallstone disease and being associated with lower transaminases. To identify common variants in ABCB4 associated with severe liver disease. We examined the association of missense and nonsense common variants (minor allele frequency >1%) at the ABCB4 locus with ALT in 412,912 Europeans from the UK Biobank using a whole-genome regression model. Next, we tested the association of the lead variant in the region with liver-related traits and incident severe liver disease in a subset of 365,449 unrelated Europeans by multiple linear/logistic regression models and Cox proportional hazards models, respectively. Analyses were adjusted for age, gender, BMI, type 2 diabetes, alcohol intake, and first 10 PCs of ancestry. We identified the ABCB4 rs1468615 T>C as the lead variant independently associated with ALT (P = 2.26 × 10−34). The rs1468615 is an intronic variant in high linkage disequilibrium with the rs2109505 (r2 = 0.94). The rs1468615 was associated with lower risk of gallstone disease (P = 8.56 × 10−12) and with lower liver enzymes (P = 2.28 × 10−30, P = 8.31 × 10−09, and P = 8.08 × 10−04 for ALT, AST, and GGT respectively). No association was found with liver cirrhosis, liver cancer, and gallbladder/biliary tract cancer. No association was found with incident severe liver disease. The rs1468615 T>C in ABCB4 confers protection against gallstone disease but not against the development of severe liver disease. [ABSTRACT FROM AUTHOR]

Programmed cell death 1/programmed cell death-ligand 1 (PD-1/PDL-1) axis has been reported to modulate liver inflammation and progression to hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). Here, we examined whether the PDCD1 variation associates with NAFLD severity in individuals with liver biopsy. We examined the impact of PDCD1 gene variants on HCC, as robust severe liver disease phenotype in UK Biobank participants. The strongest genetic association with the rs13023138 G>C variation was subsequently tested for association with liver damage in 2,889 individuals who underwent liver biopsy for suspected nonalcoholic steatohepatitis (NASH). Hepatic transcriptome was examined by RNASeq in a subset of NAFLD individuals (n=121). Transcriptomic and deconvolution analyses were performed to identify biological pathways modulated by the risk allele. The rs13023138 C>G showed the most robust association with HCC in UK Biobank (P = 5.28E-4, OR=1.32, 95% CI [1.1, 1.5]). In the liver biopsy cohort, rs13023138 G allele was independently associated with severe steatosis (OR 1.17, 95%C.I. 1.02-1.34; p=0.01), NASH (OR 1.22, 95%C.I. 1.09-1.37; p<0.001) and advanced fibrosis (OR 1.26, 95%C.I. 1.06-1.50; p=0.07). At deconvolution analysis, rs13023138 G>C allele was linked to higher hepatic representation of M1 macrophages, paralleled by upregulation of pathways related to inflammation and higher expression of CXCR6. The PDCD1 rs13023138 G allele was associated with HCC development in general population and with liver disease severity in patients at high risk of NASH. [ABSTRACT FROM AUTHOR]

Fatty liver disease (FLD) related to metabolic dysfunction and excessive alcohol affects almost one third of the global population and is a leading cause of liver related mortality. The PNPLA3 p.I148M variant accounts for the largest fraction of FLD heritability. Although women are protected during the reproductive age, especially after menopause some are susceptible to FLD, but this sexual dimorphism is neglected in clinical studies. The aim was to examine the PNPLA3 p.I148M*female sex interaction in FLD development, and to investigate the underlying mechanism. The female sex* PNPLA3 p.I148M interaction on FLD was tested in the Liver Biopsy (n=1861), severe FLD case-control (n=4374), Liver-Bible-2021 (n=817) and UK Biobank (n=347,127) cohorts. PNPLA3 expression was determined in transcriptomic cohort (n=107). HepG2 cells were used for estrogen receptor (ER) modulation and fatty acid treatment, and to generate PNPLA3-ER element (ERE) knock-out clones. In all cohorts we observed an interaction between female sex and PNPLA3 p.I148M, but not other FLD genetic risk variants, in determining FLD development and progression, with a larger effect in postmenopausal women (p<0.05). Higher hepatic PNPLA3 mRNA expression was independently associated with the p.I148M variant and female sex (p=0.002 and p=0.007, respectively). At chromatin immunoprecipitation, ERα agonists induced the ER binding to a specific ERE at a PNPLA3 enhancer site, enhancing its transcriptional activity at luciferase assays. PNPLA3 mRNA and protein expression was upregulated via direct ERα agonists, leading to intracellular fat accumulation in p.I148M homozygous HepG2 cells, but not in wild-type hepatocytes. Genetic deletion of the PNPLA3-ERE by Crispr/Cas9 editing in HepG2 abolished the ERα-induced PNPLA3 and intracellular lipid accumulation in response to fatty acids. We identified a driver of FLD acceleration occurring in a subset of women with metabolic dysfunction at menopause, highlighting at the same time a therapeutic target of particular relevance. [ABSTRACT FROM AUTHOR]