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High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.

Goyette P, Boucher G, Mallon D, Ellinghaus E, Jostins L, Huang H, Ripke S, Gusareva ES, Annese V, Hauser SL, Oksenberg JR, Thomsen I, Leslie S, International Inflammatory Bowel Disease Genetics ConsortiumAustralia and New Zealand IBDGCBelgium IBD Genetics ConsortiumItalian Group for IBD Genetic ConsortiumNIDDK Inflammatory Bowel Disease Genetics ConsortiumUnited Kingdom IBDGCWellcome Trust Case Control ConsortiumQuebec IBD Genetics ConsortiumDaly MJ, Van Steen K, Duerr RH, Barrett JC, McGovern DP, Schumm LP, Traherne JA, Carrington MN, Kosmoliaptsis V, Karlsen TH, Franke A, Rioux JD - Nat. Genet. (2015)

Bottom Line: Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles.To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis.Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

View Article: PubMed Central - PubMed

Affiliation: Research Center, Montreal Heart Institute, Montreal, Quebec, Canada.

ABSTRACT
Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

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Correlated association signals at HLA alleles support potential alternate association models for both CD and UCEquivalence of effect at the different study-wide significant associated 4-digit HLA alleles is shown for (a) CD and (b) UC. The structures illustrated in the figure are not classically defined haplotype structures, but were identified entirely based on the correlation of signal defined through pairwise reciprocal conditional logistic regression analyses (see Supplementary tables 2 and 3); although such correlations are clearly dependent on the underlying haplotypic structure of the region. Alleles identified as primary tags for independent association signals in our HLA-DRB1 focused models are shown in light blue boxes, while alternate alleles with equivalent effects are shown in grey boxes. Alleles in white boxes show study-wide significant secondary effects that can be explained entirely by the selected HLA alleles. Alleles at the HLA-DRB3, -DRB4 and -DRB5 genes were omitted in order to simplify the display; many of the alleles at these genes show high frequency and as such are correlated to many different alleles (both risk and protective) at the other class II genes. Of note, the HLA-DRB4* allele is the second strongest associated allele in UC (see Supplementary table 3).
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Figure 3: Correlated association signals at HLA alleles support potential alternate association models for both CD and UCEquivalence of effect at the different study-wide significant associated 4-digit HLA alleles is shown for (a) CD and (b) UC. The structures illustrated in the figure are not classically defined haplotype structures, but were identified entirely based on the correlation of signal defined through pairwise reciprocal conditional logistic regression analyses (see Supplementary tables 2 and 3); although such correlations are clearly dependent on the underlying haplotypic structure of the region. Alleles identified as primary tags for independent association signals in our HLA-DRB1 focused models are shown in light blue boxes, while alternate alleles with equivalent effects are shown in grey boxes. Alleles in white boxes show study-wide significant secondary effects that can be explained entirely by the selected HLA alleles. Alleles at the HLA-DRB3, -DRB4 and -DRB5 genes were omitted in order to simplify the display; many of the alleles at these genes show high frequency and as such are correlated to many different alleles (both risk and protective) at the other class II genes. Of note, the HLA-DRB4* allele is the second strongest associated allele in UC (see Supplementary table 3).

Mentions: We thus examined an HLA-DRB1-centric model and identified seven HLA-DRB1 alleles with independent effects on CD risk (study-wide significance threshold of 5×10−6) (Supplementary Table 2). Moreover, when controlling for these seven HLA-DRB1 alleles, we identified only a single additional class II allele (HLA-DPA1*01:03) independently associated with CD. Using the same conditional logistic regression framework for the analysis of the class I locus, we identified seven class I HLA alleles that are significantly associated with CD, after conditioning on the eight class II alleles (Fig. 3 and Supplementary Table 2). This HLA-DRB1-centric model explains about 2% of disease variance (Fig. 2). In UC, we identified a total of 12 HLA-DRB1 alleles, 1 HLA-DPB1 allele and 3 class I alleles (Supplementary Table 3) that can explain the association to the MHC and which account for about 5% of disease variance (Fig. 2).


High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.

Goyette P, Boucher G, Mallon D, Ellinghaus E, Jostins L, Huang H, Ripke S, Gusareva ES, Annese V, Hauser SL, Oksenberg JR, Thomsen I, Leslie S, International Inflammatory Bowel Disease Genetics ConsortiumAustralia and New Zealand IBDGCBelgium IBD Genetics ConsortiumItalian Group for IBD Genetic ConsortiumNIDDK Inflammatory Bowel Disease Genetics ConsortiumUnited Kingdom IBDGCWellcome Trust Case Control ConsortiumQuebec IBD Genetics ConsortiumDaly MJ, Van Steen K, Duerr RH, Barrett JC, McGovern DP, Schumm LP, Traherne JA, Carrington MN, Kosmoliaptsis V, Karlsen TH, Franke A, Rioux JD - Nat. Genet. (2015)

Correlated association signals at HLA alleles support potential alternate association models for both CD and UCEquivalence of effect at the different study-wide significant associated 4-digit HLA alleles is shown for (a) CD and (b) UC. The structures illustrated in the figure are not classically defined haplotype structures, but were identified entirely based on the correlation of signal defined through pairwise reciprocal conditional logistic regression analyses (see Supplementary tables 2 and 3); although such correlations are clearly dependent on the underlying haplotypic structure of the region. Alleles identified as primary tags for independent association signals in our HLA-DRB1 focused models are shown in light blue boxes, while alternate alleles with equivalent effects are shown in grey boxes. Alleles in white boxes show study-wide significant secondary effects that can be explained entirely by the selected HLA alleles. Alleles at the HLA-DRB3, -DRB4 and -DRB5 genes were omitted in order to simplify the display; many of the alleles at these genes show high frequency and as such are correlated to many different alleles (both risk and protective) at the other class II genes. Of note, the HLA-DRB4* allele is the second strongest associated allele in UC (see Supplementary table 3).
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Related In: Results  -  Collection

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Figure 3: Correlated association signals at HLA alleles support potential alternate association models for both CD and UCEquivalence of effect at the different study-wide significant associated 4-digit HLA alleles is shown for (a) CD and (b) UC. The structures illustrated in the figure are not classically defined haplotype structures, but were identified entirely based on the correlation of signal defined through pairwise reciprocal conditional logistic regression analyses (see Supplementary tables 2 and 3); although such correlations are clearly dependent on the underlying haplotypic structure of the region. Alleles identified as primary tags for independent association signals in our HLA-DRB1 focused models are shown in light blue boxes, while alternate alleles with equivalent effects are shown in grey boxes. Alleles in white boxes show study-wide significant secondary effects that can be explained entirely by the selected HLA alleles. Alleles at the HLA-DRB3, -DRB4 and -DRB5 genes were omitted in order to simplify the display; many of the alleles at these genes show high frequency and as such are correlated to many different alleles (both risk and protective) at the other class II genes. Of note, the HLA-DRB4* allele is the second strongest associated allele in UC (see Supplementary table 3).
Mentions: We thus examined an HLA-DRB1-centric model and identified seven HLA-DRB1 alleles with independent effects on CD risk (study-wide significance threshold of 5×10−6) (Supplementary Table 2). Moreover, when controlling for these seven HLA-DRB1 alleles, we identified only a single additional class II allele (HLA-DPA1*01:03) independently associated with CD. Using the same conditional logistic regression framework for the analysis of the class I locus, we identified seven class I HLA alleles that are significantly associated with CD, after conditioning on the eight class II alleles (Fig. 3 and Supplementary Table 2). This HLA-DRB1-centric model explains about 2% of disease variance (Fig. 2). In UC, we identified a total of 12 HLA-DRB1 alleles, 1 HLA-DPB1 allele and 3 class I alleles (Supplementary Table 3) that can explain the association to the MHC and which account for about 5% of disease variance (Fig. 2).

Bottom Line: Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles.To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis.Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

View Article: PubMed Central - PubMed

Affiliation: Research Center, Montreal Heart Institute, Montreal, Quebec, Canada.

ABSTRACT
Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

Show MeSH
Related in: MedlinePlus