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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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Comparison of odds ratio in CD and UC for HLA alleles identified from HLA-focused modelsOdds ratio (OR) from the primary univariate association analyses in CD and UC for all alleles identified in the HLA-focused models of CD and/or UC are presented with 95% confidence intervals (a). Odds ratio for CD and UC are in blue and red respectively; darker colors indicate study-wide significant effect (P<5×10−6), lighter colors indicate nominal significance level (0.05>P 5×10−6) and white indicates non-significance (P 0.05) (for specific effect and significance values refer to Fig. 3 and Supplementary Tables 2 and 3). Allele HLA-B*52:01 is indicated for UC in place of the equivalent HLA-C*12:02 to simplify the display of this shared signal. For the same HLA alleles, odds ratio (with 95% confidence intervals) for an IBD analysis are plotted against the odds ratio for the CD versus UC analysis with the IBD risk allele as the reference (b). Empty circles represent variants where the absence of the allele is the reference. Alleles identified as significant in CD or UC only are plotted in blue and red, respectively. Variants identified as significant in both are shown in purple. To be noted, HLA-DRB1*07:01 and HLA-DRB1*13:02 have opposite direction of effect between CD and UC. Shared association signals are expected to fall in the upper triangle of the plot. Most variants fall outside of this region, highlighting the difference between CD and UC in the MHC.
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Figure 6: Comparison of odds ratio in CD and UC for HLA alleles identified from HLA-focused modelsOdds ratio (OR) from the primary univariate association analyses in CD and UC for all alleles identified in the HLA-focused models of CD and/or UC are presented with 95% confidence intervals (a). Odds ratio for CD and UC are in blue and red respectively; darker colors indicate study-wide significant effect (P<5×10−6), lighter colors indicate nominal significance level (0.05>P 5×10−6) and white indicates non-significance (P 0.05) (for specific effect and significance values refer to Fig. 3 and Supplementary Tables 2 and 3). Allele HLA-B*52:01 is indicated for UC in place of the equivalent HLA-C*12:02 to simplify the display of this shared signal. For the same HLA alleles, odds ratio (with 95% confidence intervals) for an IBD analysis are plotted against the odds ratio for the CD versus UC analysis with the IBD risk allele as the reference (b). Empty circles represent variants where the absence of the allele is the reference. Alleles identified as significant in CD or UC only are plotted in blue and red, respectively. Variants identified as significant in both are shown in purple. To be noted, HLA-DRB1*07:01 and HLA-DRB1*13:02 have opposite direction of effect between CD and UC. Shared association signals are expected to fall in the upper triangle of the plot. Most variants fall outside of this region, highlighting the difference between CD and UC in the MHC.

Mentions: Although there is a significant challenge in defining the causal alleles for CD and UC in the MHC given the LD structure in the region, a number of conclusions can be drawn regardless of the models tested. First, the high density mapping of this region in a large cohort revealed the significant contribution of the MHC to disease risk, a contribution that is not apparent in the previous GWAS. Second, for both CD and UC it would appear that variation within HLA genes as opposed to variation in other genes within the MHC plays a predominant role in disease susceptibility. Third, while the contribution of class I and class II HLA variants to disease risk is relatively equivalent in CD, HLA class II variation plays a more important role in UC. Fourth, in contrast to the majority of non-MHC susceptibility loci being shared between CD and UC, most associated HLA alleles have a predominant role in either CD or UC, with very few having shared IBD risk Fig. 6). Finally, the decreased heterozygosity in UC suggests that the ability to recognize a broader set of antigens, potentially of colonic microbial origin, is important to mount protective immunity.


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)

Comparison of odds ratio in CD and UC for HLA alleles identified from HLA-focused modelsOdds ratio (OR) from the primary univariate association analyses in CD and UC for all alleles identified in the HLA-focused models of CD and/or UC are presented with 95% confidence intervals (a). Odds ratio for CD and UC are in blue and red respectively; darker colors indicate study-wide significant effect (P<5×10−6), lighter colors indicate nominal significance level (0.05>P 5×10−6) and white indicates non-significance (P 0.05) (for specific effect and significance values refer to Fig. 3 and Supplementary Tables 2 and 3). Allele HLA-B*52:01 is indicated for UC in place of the equivalent HLA-C*12:02 to simplify the display of this shared signal. For the same HLA alleles, odds ratio (with 95% confidence intervals) for an IBD analysis are plotted against the odds ratio for the CD versus UC analysis with the IBD risk allele as the reference (b). Empty circles represent variants where the absence of the allele is the reference. Alleles identified as significant in CD or UC only are plotted in blue and red, respectively. Variants identified as significant in both are shown in purple. To be noted, HLA-DRB1*07:01 and HLA-DRB1*13:02 have opposite direction of effect between CD and UC. Shared association signals are expected to fall in the upper triangle of the plot. Most variants fall outside of this region, highlighting the difference between CD and UC in the MHC.
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Related In: Results  -  Collection

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Figure 6: Comparison of odds ratio in CD and UC for HLA alleles identified from HLA-focused modelsOdds ratio (OR) from the primary univariate association analyses in CD and UC for all alleles identified in the HLA-focused models of CD and/or UC are presented with 95% confidence intervals (a). Odds ratio for CD and UC are in blue and red respectively; darker colors indicate study-wide significant effect (P<5×10−6), lighter colors indicate nominal significance level (0.05>P 5×10−6) and white indicates non-significance (P 0.05) (for specific effect and significance values refer to Fig. 3 and Supplementary Tables 2 and 3). Allele HLA-B*52:01 is indicated for UC in place of the equivalent HLA-C*12:02 to simplify the display of this shared signal. For the same HLA alleles, odds ratio (with 95% confidence intervals) for an IBD analysis are plotted against the odds ratio for the CD versus UC analysis with the IBD risk allele as the reference (b). Empty circles represent variants where the absence of the allele is the reference. Alleles identified as significant in CD or UC only are plotted in blue and red, respectively. Variants identified as significant in both are shown in purple. To be noted, HLA-DRB1*07:01 and HLA-DRB1*13:02 have opposite direction of effect between CD and UC. Shared association signals are expected to fall in the upper triangle of the plot. Most variants fall outside of this region, highlighting the difference between CD and UC in the MHC.
Mentions: Although there is a significant challenge in defining the causal alleles for CD and UC in the MHC given the LD structure in the region, a number of conclusions can be drawn regardless of the models tested. First, the high density mapping of this region in a large cohort revealed the significant contribution of the MHC to disease risk, a contribution that is not apparent in the previous GWAS. Second, for both CD and UC it would appear that variation within HLA genes as opposed to variation in other genes within the MHC plays a predominant role in disease susceptibility. Third, while the contribution of class I and class II HLA variants to disease risk is relatively equivalent in CD, HLA class II variation plays a more important role in UC. Fourth, in contrast to the majority of non-MHC susceptibility loci being shared between CD and UC, most associated HLA alleles have a predominant role in either CD or UC, with very few having shared IBD risk Fig. 6). Finally, the decreased heterozygosity in UC suggests that the ability to recognize a broader set of antigens, potentially of colonic microbial origin, is important to mount protective immunity.

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