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, Oct 09, 2015
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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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    ABSTRACT: IL-12 and IL-23 cytokines respectively drive Th1 and Th17 type responses. Yet, little is known regarding the biology of these receptors. As the IL-12 and IL-23 receptors share a common subunit, it has been assumed that these receptors are co-expressed. Surprisingly, we find that the expression of each of these receptors is restricted to specific cell types, in both mouse and human. Indeed, although IL-12Rβ2 is expressed by NK cells and a subset of γδ T cells, the expression of IL-23R is restricted to specific T cell subsets, a small number of B cells and innate lymphoid cells. By exploiting an IL-12- and IL-23-dependent mouse model of innate inflammation, we demonstrate an intricate interplay between IL-12Rβ2 NK cells and IL-23R innate lymphoid cells with respectively dominant roles in the regulation of systemic versus local inflammatory responses. Together, these findings support an unforeseen lineage-specific dichotomy in the in vivo role of both the IL-12 and IL-23 pathways in pathological inflammatory states, which may allow more accurate dissection of the roles of these receptors in chronic inflammatory diseases in humans.
    PLoS ONE 02/2014; 9(2):e89092. DOI:10.1371/journal.pone.0089092 · 3.23 Impact Factor
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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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    ABSTRACT: Genetic studies of human diseases have identified multiple genetic risk loci for various fibrotic diseases. This has provided insights into the myriad of biological pathways potentially involved in disease pathogenesis. These discoveries suggest that alterations in immune responses, barrier function, metabolism and telomerase activity may be implicated in the genetic risks for fibrotic diseases. In addition to genetic disease-risks, the identification of genetic disease-modifiers associated with disease complications, severity or prognosis provides crucial insights into the biological processes implicated in disease progression. Understanding the biological processes driving disease progression may be critical to delineate more effective strategies for therapeutic interventions. This review provides an overview of current knowledge and gaps regarding genetic disease-risks and genetic disease-modifiers in human fibrotic diseases.
    Frontiers in Pharmacology 12/2013; 4:159. DOI:10.3389/fphar.2013.00159 · 3.80 Impact Factor
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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.
    PLoS ONE 11/2013; 8(11):e79580. DOI:10.1371/journal.pone.0079580 · 3.23 Impact Factor
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