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

Academic Department of Medical Genetics, Cambridge University, Cambridge, UK
Nature Genetics (Impact Factor: 29.35). 03/2011; 43(4):329-32. DOI: 10.1038/ng.789
Source: PubMed


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). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10⁻⁸) and replicated all previously associated loci. We identified three further new loci in a 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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Available from: Katherine I Morley
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    • "Similarly, genetic polymorphisms in IL12RB2 are also associated with increased risk of chronic inflammatory disease. Notably, a recent GWA study of primary biliary cirrhosis revealed an association with IL12RB2, IL12A (a gene encoding for the p35 subunit of the IL-12 cytokines) and STAT4 (downstream of IL12RB2) [9], [15]. Genetic polymorphisms in both the IL-12 and IL-23 pathways are thus strongly associated with susceptibility to inflammatory diseases. "
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    • "The genetic architecture of autoimminue liver diseases such as Primary Sclerosing Cholangitis (PSC) and Primary Biliary Cirrhosis (PBC) was recently studied through a series of GWAS (Hirschfield et al., 2009; Liu et al., 2010; Mells et al., 2011; Melum et al., 2011; Liu et al., 2013a,b). Inflammation and tissue damage is thought to trigger sustained aberrant tissue repair responses that ultimately lead to the replacement of the organ by scar fibrotic tissue. "
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    • "Our data confirmed that HLA-DR*08, *0801, and *0803 were potential risk factors for PBC (corresponding serological type DR8). Previous studies indicated that HLA-DR8 was significantly associated with PBC, with ORs ranging from 2.4 to 3.3 based on the population examined [49]. In contrast, several reports have failed to confirm this association [30,33]. "
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    ABSTRACT: Several previous studies suggested that HLA-Class II may be associated with susceptibility to primary biliary cirrhosis (PBC), but data from individual studies remain controversial. Therefore, a systematic review and meta-analysis is needed to comprehensively evaluate the association between HLA-Class II and PBC risk. All published reports of an association between HLA class II and PBC risk were searched in PubMed, EMBASE (updated to 22 May 2012). ORs with 95% confidence intervals (CIs) were extracted from each included study and the meta-analysis was performed using the fixed- or random-effects model. A total of 3,732 PBC patients and 11,031 controls from 34 studies were included in the meta-analysis. An assessment of study quality revealed that the majority of studies included (18 studies) were of high quality. The serological group DR8 was found to be a risk factor for PBC (OR = 2.82, 95%CI: 1.84-4.30). At the allelic level, HLA-DR*08 and HLA-DR*0801 were identified as risk factors for PBC (OR = 2.30, 95%CI: 1.76-3.00; OR = 3.23, 95%CI: 2.22-4.70, respectively), whereas HLA-DR*11 and HLA-DR*13 were potent protective factors (OR = 0.31, 95%CI: 0.27-0.38; OR = 0.62, 95%CI: 0.48-0.81, respectively). HLA-DQB1 and HLA-DQB1*0402 conferred a predisposition to PBC development (OR = 3.47, 95%CI: 2.35-5.13), whereas HLA-DQB1*0604 was protective against PBC (OR = 0.3, 95%CI: 0.18-0.58). No HLA-DPB1 allele was observed to be associated with PBC susceptibility (P > 0.05). The present study revealed that HLA-Class II components are closely associated with the development of PBC.
    Preview · Article · Nov 2013 · PLoS ONE
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