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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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Variance explained by 4-digit HLA alleles in CD and UCProportion of variance explained on a logit scale (McKelvey and Zavoina’s Pseudo R2, see Online Methods) for different models in CD (left) and UC (right). The top boxes show the variance explained by previously identified GWAS index SNPs within the MHC4. The middle boxes illustrate the variance explained by HLA models including all 4-digit alleles of frequency > 0.5% (126 alleles in CD and UC) and models restricted to 4-digit alleles within either class I (63 alleles) or class II regions (63 alleles), respectively. The Venn diagram illustrates the proportion of variance explained that is unique to class I, class II or shared. The bottom boxes indicate the variance explained by the proposed HLA models (15 and 16 alleles in CD and UC, respectively). To be noted, these estimations of variance explained were performed on the logit scale for practical reasons, and should not be directly compared to heritability estimates computed on the (Gaussian) liability scale.
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Figure 2: Variance explained by 4-digit HLA alleles in CD and UCProportion of variance explained on a logit scale (McKelvey and Zavoina’s Pseudo R2, see Online Methods) for different models in CD (left) and UC (right). The top boxes show the variance explained by previously identified GWAS index SNPs within the MHC4. The middle boxes illustrate the variance explained by HLA models including all 4-digit alleles of frequency > 0.5% (126 alleles in CD and UC) and models restricted to 4-digit alleles within either class I (63 alleles) or class II regions (63 alleles), respectively. The Venn diagram illustrates the proportion of variance explained that is unique to class I, class II or shared. The bottom boxes indicate the variance explained by the proposed HLA models (15 and 16 alleles in CD and UC, respectively). To be noted, these estimations of variance explained were performed on the logit scale for practical reasons, and should not be directly compared to heritability estimates computed on the (Gaussian) liability scale.

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)

Variance explained by 4-digit HLA alleles in CD and UCProportion of variance explained on a logit scale (McKelvey and Zavoina’s Pseudo R2, see Online Methods) for different models in CD (left) and UC (right). The top boxes show the variance explained by previously identified GWAS index SNPs within the MHC4. The middle boxes illustrate the variance explained by HLA models including all 4-digit alleles of frequency > 0.5% (126 alleles in CD and UC) and models restricted to 4-digit alleles within either class I (63 alleles) or class II regions (63 alleles), respectively. The Venn diagram illustrates the proportion of variance explained that is unique to class I, class II or shared. The bottom boxes indicate the variance explained by the proposed HLA models (15 and 16 alleles in CD and UC, respectively). To be noted, these estimations of variance explained were performed on the logit scale for practical reasons, and should not be directly compared to heritability estimates computed on the (Gaussian) liability scale.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4310771&req=5

Figure 2: Variance explained by 4-digit HLA alleles in CD and UCProportion of variance explained on a logit scale (McKelvey and Zavoina’s Pseudo R2, see Online Methods) for different models in CD (left) and UC (right). The top boxes show the variance explained by previously identified GWAS index SNPs within the MHC4. The middle boxes illustrate the variance explained by HLA models including all 4-digit alleles of frequency > 0.5% (126 alleles in CD and UC) and models restricted to 4-digit alleles within either class I (63 alleles) or class II regions (63 alleles), respectively. The Venn diagram illustrates the proportion of variance explained that is unique to class I, class II or shared. The bottom boxes indicate the variance explained by the proposed HLA models (15 and 16 alleles in CD and UC, respectively). To be noted, these estimations of variance explained were performed on the logit scale for practical reasons, and should not be directly compared to heritability estimates computed on the (Gaussian) liability scale.
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