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      Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases

      1 , 2 , 3 , 4 , 5

      Hepatology

      Wiley

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          Primary biliary cirrhosis.

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            Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

            In addition to the HLA-locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). Twenty-eight loci were followed up in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 novel risk loci (P<5×10−8) and replicated all previously associated loci. Three further novel loci were identified by meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A, and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.
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              Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants.

              Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown. To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis. We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major histocompatibility complex class II, DQ beta chain 1) had the strongest association (P=1.78x10(-19); odds ratio for patients vs. controls, 1.75). Primary biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the IL12A locus (encoding interleukin-12alpha), rs6441286 (P=2.42x10(-14); odds ratio, 1.54) and rs574808 (P=1.88x10(-13); odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor beta2), rs3790567 (P=2.76x10(-11); odds ratio, 1.51). Fine-mapping analysis showed that a five-allele haplotype in the 3' flank of IL12A was significantly associated with primary biliary cirrhosis (P=1.15x10(-34)). We found a modest genomewide association (P<5.0x10(-5)) with the risk of disease for SNPs at the STAT4 locus (encoding signal transducer and activator of transcription 4) and the CTLA4 locus (encoding cytotoxic T-lymphocyte-associated protein 4) and 10 other loci. Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of primary biliary cirrhosis. (ClinicalTrials.gov number, NCT00242125.) 2009 Massachusetts Medical Society
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                Author and article information

                Journal
                Hepatology
                Hepatology
                Wiley
                0270-9139
                1527-3350
                November 06 2018
                November 06 2018
                Affiliations
                [1 ]Arizona State UniversityDivision of Gastroenterology and HepatologyMayo Clinic Phoenix AZ
                [2 ]University of California Davis, Sacramento CA
                [3 ]Yale School of Medicine New Haven CT
                [4 ]University of Miami Miami FL
                [5 ]University of Texas Southwestern Medical Center Dallas TX
                Article
                10.1002/hep.30145
                30070375
                ace989bb-d90f-473f-89e4-cade18a37876
                © 2018

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