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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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Primary univariate association analyses of CD and UCUnivariate association analysis results for 8,939 SNPs (dark grey) (Supplementary Table 12), 90 2-digit and 138 4-digit resolution HLA alleles (yellow) (Supplementary Table 13), as well as 741 single amino acid variants (red) (Supplementary Table 4) in the MHC region are shown for 18,405 CD cases and 14,308 UC cases (with 34,241 common control subjects). Given that previous genetic analyses have identified distinct effects in the MHC for CD and UC, with different non-correlated alleles identified in each disease, we opted to perform the finemapping analyses for CD and UC separately. (a) The primary univariate association analysis in CD reveals over 1,789 markers showing study-wide significant association (P<5×10−6) across the MHC, including 32 4-digit resolution classical HLA alleles (Fig. 3 and Supplementary Table 2). The single most significant variant for CD is HLA-DRB1*01:03 (P=3×10−62, OR= 2.51). (b) The primary univariate association analysis in UC reveals over 2,762 markers showing study-wide significant association across the MHC, including 50 4-digit resolution classical HLA alleles (Fig. 3 and Supplementary Table 3). The single most significant variant for UC is rs6927022 (P=8×10−154, OR= 1.49) while the best HLA allele is HLA-DRB1*01:03 (P=3×10−119, OR=3.59); each acting independently. Twenty-nine SNPs and 9 amino acid variants surpass HLA-DRB1*01:03 as the next most significant variants in the primary analysis however all of these are correlated to rs6927022 and their significance is dramatically reduced by conditional logistic regression.
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Figure 1: Primary univariate association analyses of CD and UCUnivariate association analysis results for 8,939 SNPs (dark grey) (Supplementary Table 12), 90 2-digit and 138 4-digit resolution HLA alleles (yellow) (Supplementary Table 13), as well as 741 single amino acid variants (red) (Supplementary Table 4) in the MHC region are shown for 18,405 CD cases and 14,308 UC cases (with 34,241 common control subjects). Given that previous genetic analyses have identified distinct effects in the MHC for CD and UC, with different non-correlated alleles identified in each disease, we opted to perform the finemapping analyses for CD and UC separately. (a) The primary univariate association analysis in CD reveals over 1,789 markers showing study-wide significant association (P<5×10−6) across the MHC, including 32 4-digit resolution classical HLA alleles (Fig. 3 and Supplementary Table 2). The single most significant variant for CD is HLA-DRB1*01:03 (P=3×10−62, OR= 2.51). (b) The primary univariate association analysis in UC reveals over 2,762 markers showing study-wide significant association across the MHC, including 50 4-digit resolution classical HLA alleles (Fig. 3 and Supplementary Table 3). The single most significant variant for UC is rs6927022 (P=8×10−154, OR= 1.49) while the best HLA allele is HLA-DRB1*01:03 (P=3×10−119, OR=3.59); each acting independently. Twenty-nine SNPs and 9 amino acid variants surpass HLA-DRB1*01:03 as the next most significant variants in the primary analysis however all of these are correlated to rs6927022 and their significance is dramatically reduced by conditional logistic regression.

Mentions: As a first step to defining the nature of the association to CD and UC within the MHC, we performed univariate analyses of the SNPs, classical HLA alleles, and HLA amino acids. These analyses revealed a very large number of variants across the MHC region with significant association to these phenotypes (Fig. 1), with major peaks of association centered in and around the classical HLA genes, suggesting a role for classical HLA alleles in CD and UC risk. This observation is consistent with gene-based analyses, which show strong association at the HLA genes for both UC and CD (e.g. P<1×10−300 for HLA-DRB1 in UC) (Supplementary Table 1). In particular, these analyses demonstrated a role of HLA-DRB1 that cannot be attributed to other HLA genes, with evidence of residual association in class I and class II regions (Supplementary Table 1). In order to be more quantitative, we calculated the variance explained by the class I and class II alleles. Whereas the contribution of class I and class II alleles are relatively equivalent in CD, not only is the overall impact of HLA on disease risk greater in UC, but the alleles in the class II region have nearly three-fold greater impact than class I alleles (Fig. 2). Moreover, these analyses have revealed that classical HLA alleles explain three- to ten-fold more of the disease variance than that explained by the index SNPs that were previously identified (~3% vs ~0.3% in CD; ~6% vs ~2% in UC) (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)

Primary univariate association analyses of CD and UCUnivariate association analysis results for 8,939 SNPs (dark grey) (Supplementary Table 12), 90 2-digit and 138 4-digit resolution HLA alleles (yellow) (Supplementary Table 13), as well as 741 single amino acid variants (red) (Supplementary Table 4) in the MHC region are shown for 18,405 CD cases and 14,308 UC cases (with 34,241 common control subjects). Given that previous genetic analyses have identified distinct effects in the MHC for CD and UC, with different non-correlated alleles identified in each disease, we opted to perform the finemapping analyses for CD and UC separately. (a) The primary univariate association analysis in CD reveals over 1,789 markers showing study-wide significant association (P<5×10−6) across the MHC, including 32 4-digit resolution classical HLA alleles (Fig. 3 and Supplementary Table 2). The single most significant variant for CD is HLA-DRB1*01:03 (P=3×10−62, OR= 2.51). (b) The primary univariate association analysis in UC reveals over 2,762 markers showing study-wide significant association across the MHC, including 50 4-digit resolution classical HLA alleles (Fig. 3 and Supplementary Table 3). The single most significant variant for UC is rs6927022 (P=8×10−154, OR= 1.49) while the best HLA allele is HLA-DRB1*01:03 (P=3×10−119, OR=3.59); each acting independently. Twenty-nine SNPs and 9 amino acid variants surpass HLA-DRB1*01:03 as the next most significant variants in the primary analysis however all of these are correlated to rs6927022 and their significance is dramatically reduced by conditional logistic regression.
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Related In: Results  -  Collection

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Figure 1: Primary univariate association analyses of CD and UCUnivariate association analysis results for 8,939 SNPs (dark grey) (Supplementary Table 12), 90 2-digit and 138 4-digit resolution HLA alleles (yellow) (Supplementary Table 13), as well as 741 single amino acid variants (red) (Supplementary Table 4) in the MHC region are shown for 18,405 CD cases and 14,308 UC cases (with 34,241 common control subjects). Given that previous genetic analyses have identified distinct effects in the MHC for CD and UC, with different non-correlated alleles identified in each disease, we opted to perform the finemapping analyses for CD and UC separately. (a) The primary univariate association analysis in CD reveals over 1,789 markers showing study-wide significant association (P<5×10−6) across the MHC, including 32 4-digit resolution classical HLA alleles (Fig. 3 and Supplementary Table 2). The single most significant variant for CD is HLA-DRB1*01:03 (P=3×10−62, OR= 2.51). (b) The primary univariate association analysis in UC reveals over 2,762 markers showing study-wide significant association across the MHC, including 50 4-digit resolution classical HLA alleles (Fig. 3 and Supplementary Table 3). The single most significant variant for UC is rs6927022 (P=8×10−154, OR= 1.49) while the best HLA allele is HLA-DRB1*01:03 (P=3×10−119, OR=3.59); each acting independently. Twenty-nine SNPs and 9 amino acid variants surpass HLA-DRB1*01:03 as the next most significant variants in the primary analysis however all of these are correlated to rs6927022 and their significance is dramatically reduced by conditional logistic regression.
Mentions: As a first step to defining the nature of the association to CD and UC within the MHC, we performed univariate analyses of the SNPs, classical HLA alleles, and HLA amino acids. These analyses revealed a very large number of variants across the MHC region with significant association to these phenotypes (Fig. 1), with major peaks of association centered in and around the classical HLA genes, suggesting a role for classical HLA alleles in CD and UC risk. This observation is consistent with gene-based analyses, which show strong association at the HLA genes for both UC and CD (e.g. P<1×10−300 for HLA-DRB1 in UC) (Supplementary Table 1). In particular, these analyses demonstrated a role of HLA-DRB1 that cannot be attributed to other HLA genes, with evidence of residual association in class I and class II regions (Supplementary Table 1). In order to be more quantitative, we calculated the variance explained by the class I and class II alleles. Whereas the contribution of class I and class II alleles are relatively equivalent in CD, not only is the overall impact of HLA on disease risk greater in UC, but the alleles in the class II region have nearly three-fold greater impact than class I alleles (Fig. 2). Moreover, these analyses have revealed that classical HLA alleles explain three- to ten-fold more of the disease variance than that explained by the index SNPs that were previously identified (~3% vs ~0.3% in CD; ~6% vs ~2% in UC) (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