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HLA-DPB1-COL11A2 and Three Additional Xmhc Loci Are Independently Associated with RA in a UK Cohort

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HLA-DPB1-COL11A2 and Three Additional Xmhc Loci Are Independently Associated with RA in a UK Cohort Genes and Immunity (2011) 12, 169–175 & 2011 Macmillan Publishers Limited All rights reserved 1466-4879/11 www.nature.com/gene ORIGINAL ARTICLE HLA-DPB1-COL11A2 and three additional xMHC loci are independently associated with RA in a UK cohort G Orozco1, A Barton1, S Eyre1, B Ding2, J Worthington1,XKe1,3,4 and W Thomson1,4 1Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; 2Karolinska Institute, Stockholm, Sweden and 3Institute of Child Health, University College London, London, UK The aim of this study was to investigate the complex association pattern of the extended major histocompatibility complex (xMHC) region with rheumatoid arthritis (RA) susceptibility to identify effects independent of HLA-DRB1. A total of 1804 RA cases and 1474 controls were included. High-resolution HLA-DRB1 typing was performed. Subjects were genotyped for 1546 single-nucleotide polymorphisms (SNPs) using Affymetrix GeneChip 500 K (Santa Clara, CA, USA) as part of the Wellcome Trust Case Control Consortium Study. Statistical analysis was carried out using PLINK. To avoid confounding by RA- associated HLA-DRB1 alleles, we analyzed xMHC SNPs using a data set with pairwise matching of cases and controls on DRB1 genotypes. A total of 594 case–control pairs with identical DRB1 genotypes were identified. After this adjustment, 104 SNPs remained significantly associated with RA (Po0.05), suggesting that additional RA loci independent of HLA-DRB1 can be found in the xMHC region. Of these, four loci showed the strongest associations with RA (Po0.005): ZNF391, the olfactory receptor (OR) gene cluster, C6orf26-RDBP and HLA-DPB1-COL11A2. An additional locus mapping to the BTN (butyrophilin) cluster showed independent association with RA in anti-cyclic citrullinated peptide-positive patients exclusively. We have validated the previously described independent association of the HLA-DPB1-COL11A2 locus with RA. In addition, association with three novel independent RA loci in the xMHC region (ZNF391, OR2H1 and C6orf26-RDBP) has been detected. Genes and Immunity (2011) 12, 169–175; doi:10.1038/gene.2010.57; published online 3 February 2011 Keywords: rheumatoid arthritis; xMHC; susceptibility; HLA-DRB1 Introduction methods revealed that the association of the HLA-DRB1 locus with RA is complex, with a variety of specific Rheumatoid arthritis (RA) is a common disease, affecting alleles conferring different risks. These alleles share a around 1% of the population worldwide. It is an sequence in the third hypervariable region of the gene inflammatory, autoimmune, systemic disease and is char- termed the shared epitope.5 Since then, countless studies acterized by the chronic inflammation and progressive have demonstrated that HLA-DRB1 is consistently linked destruction of the joints that leads to disability.1 RA is a and associated with RA in every population studied.6 complex disease, meaning that multiple genetic variants, HLA-DRB1 lies within the major histocompatibility environmental factors and random events interact to trigger complex (MHC) on chromosome 6p21. The classical pathological pathways. Although many of these etiological extended MHC (MHCx) encompasses a region of factors have not yet been identified, recent groundbreaking B3.6 Mb and it is divided into three subregions (classes advances such as the availability of genome-wide associa- I, II and III), whereas the xMHC encompasses a B7.8 Mb. tion studies have expanded our knowledge about the It is characterized by its great variability and gene genetic factors that contribute to RA, such that 26 loci have density. Many of these genes have immunological now been confirmed (Po5 Â 10À8).2 functions, and variation within the MHC has been found However, the HLA-DRB1 locus identified long before to be associated with the majority of autoimmune the advent of genome-wide association studies remains diseases.7 The region is also characterized by the the major RA susceptibility locus. The association of presence of strong linkage disequilibrium (LD). HLA-DRB1 alleles with RA was described for the first A variety of approaches have been used to determine time in the 1970s.3,4 Subsequent molecular typing whether additional RA susceptibility loci reside within the MHC region, but interpretation of these associations is made difficult by the strong LD and insufficient Correspondence: Dr G Orozco, Arthritis Research UK Epidemiology coverage of the region in many of the studies.8–13 More Unit, Manchester Academic Health Science Centre, University of recently, dense single-nucleotide polymorphism (SNP)- Manchester, Stopford Building, Oxford Road, Manchester M13 9PT, mapping studies have identified several loci conferring UK. RA susceptibility independently of HLA-DRB1 risk E-mail: [email protected] 4These authors share senior authorship. alleles using novel statistical approaches to avoid Received 26 April 2010; revised and accepted 25 June 2010; confounding.14–16 Validation in independent data sets is published online 3 February 2011 particularly important to confirm new RA loci in the Association of xMHC with RA G Orozco et al 170 MHC. The Wellcome Trust Case Control Consortium HLA-G-HLA-A locus, whereas the other four showed (WTCCC) Study provides an ideal data source for this stronger evidence of individual independent effects purpose.17 In the present study, this large and well- (Supplementary Figure 2). Therefore, we have found at characterized data set was examined for the identifica- least four xMHC loci associated with RA independently tion and validation of HLA-DRB1-independent RA of HLA-DRB1: risk loci. Locus 1: close to ZNF391 in the extended class I region; Locus 2: close to OR2H1 in the extended class I region; Locus 3:closetoC6orf26-RDBP in the class III region; and Results Locus 4: HLA-DPB1-COL11A2 in the class II region. In the initial unmatched analysis, we found 745 It has been shown that HLA alleles are differentially SNPs significantly associated with RA (P trendo0.05; associated with anti-cyclic citrullinated peptide (CCP)- Figure 1a). Of these, 192 markers reached genome- positive and -negative disease. Therefore, we next wide significance (Po5 Â 10À7, as defined in the analyzed the unmatched data in anti-CCP-positive and original WTCCC Study17) and 269 were significant anti-CCP-negative patients separately. The anti-CCP þ after Bonferroni correction of the xMHC region (Po3.2 Â subgroup showed a similar pattern of association 10À5). Many of the strongest associations were observed compared with the whole data set, with the strongest in the vicinity of the HLA-DRB1 locus, although a associations around the HLA-DRB1 locus and evidence number of suggestive additional signals closer to the of additional signals (Figure 1b). On the contrary, only telomere were detected. the HLA-DRB1 region surpassed the GW significance To avoid confounding by RA-associated HLA-DRB1 threshold in the anti-CCPÀ subgroup (Figure 1c). alleles, we performed HLA-DRB1 case–control matching Next, we carried out HLA-DRB1-matched analysis at a ratio 1:1, as previously described.14 Given the stratified according to the presence or absence of anti- stringent selection strategy, we expected a decrease in CCP antibodies. A total of 296 and 119 matched case– the statistical power, as the number of individuals control pairs were available for the anti-CCP þ and anti- included in the analysis was reduced significantly (594 CCPÀ groups, respectively. Three loci were associated case–control pairs). A significance threshold was set at with anti-CCP þ RA, independently of HLA-DRB1,at Po0.005, and five loci were identified to be associated Po0.005: the butyrophilin (BTN)-gene cluster locus with RA independently of HLA-DRB1, that is, ZNF391, (particularly in the BTN2A2-BTN3A1 region), HLA-B- OR2H1-OR2H2, HLA-G-HLA-A, C6orf26-RDBP and HCP5 and HLA-DPB1-COL11A2 (Table 2 and Figure 2b). HLA-DPB1-COL11A2 (Table 1 and Figure 2a). Conditional logistic regression analysis provided sup- To further test whether these five loci represent effects port that they represented true independent effects independent of each other and the rest of the region, we (Supplementary Figure 3). In addition, the olfactory performed conditional logistic regression analysis for the receptor (OR) locus could also represent another strongest associated SNP within each locus, conditioning independent effect (P ¼ 0.007) (Figure 2b). With regard on all the SNPs analyzed across the xMHC region. to the anti-CCP-patient subgroup, ZNF391, the OR This analysis also allows the visual display of the in- cluster, and HLA-DPB1-COL11A2 showed some evi- dependence of a locus (a dip and/or a spike against dence of association with RA (P ¼ 0.01), but the weaker the xMHC), as shown in Supplementary Figure 2. A association was primarily due to the smaller sample very complex association pattern was found for the size, in comparison with the anti-CCP þ subgroup 80 80 70 70 60 60 50 50 40 40 -logP -logP 30 30 20 20 10 10 0 0 25700 26700 27700 28700 29700 30700 31700 32700 2570026700 27700 28700 29700 30700 31700 32700 Position on Chr6 (Kb) Position on Chr6 (Kb) 8 7 6 5 4 -logP 3 2 1 0 2570026700 27700 28700 29700 30700 31700 32700 Position on Chr6 (Kb) Figure 1 Unmatched association analysis of 1546 SNPs in the xMHC region using the whole RA cohort (1804 RA patients and 1474controls) (a), anti-CCP þ (1042 RA patients and 1804 controls) (b) and anti-CCPÀ (270 RA patients and 1804 controls) (c) patients
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