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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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HLA-DR peptide binding groove electrostatic properties and risk of IBDThe electrostatic potential of all HLA-DR alleles associated with UC or CD, and of all common HLA-DR alleles (frequency >1%), was calculated. HLA-DR alleles associated with increased or decreased risk of IBD at study wide-significance level (P< 5×10−6) are shown in dark red or dark blue, respectively. Respective risk associations at suggestive level (1×10−4<P<5×10−6) are shown in pale red and pale blue. Electrostatic potential comparisons among HLA-DR molecules were performed in a pairwise, all-versus-all, fashion (see Online Methods) to produce distance matrices that are displayed as symmetrical heatmaps (scale ranges from 0 [identical] to 1 [maximum difference]). (a) The electrostatic potential in seven regions within the peptide binding groove (see Online Methods and Supplementary Fig. 10), which interact with the presented peptide, were compared among the HLA-DR alleles and pooled onto a single Euclidian distance matrix. The distance-based clustering identifies four clusters, with an enrichment of risk alleles in two of these. Comparison of the electrostatic potential at individual peptide binding groove regions is shown in Supplementary Fig. 13. (b) Heatmap representing electrostatic potential differences among the HLA-DR alleles at a spherical region that encompasses amino acid residues 67, 70 and 71 of the HLA-DRβ chain (associated with risk for UC and CD; Supplementary Table 13). The distance-based clustering identifies two clusters that correlate with directionality of effect in IBD.
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Figure 4: HLA-DR peptide binding groove electrostatic properties and risk of IBDThe electrostatic potential of all HLA-DR alleles associated with UC or CD, and of all common HLA-DR alleles (frequency >1%), was calculated. HLA-DR alleles associated with increased or decreased risk of IBD at study wide-significance level (P< 5×10−6) are shown in dark red or dark blue, respectively. Respective risk associations at suggestive level (1×10−4<P<5×10−6) are shown in pale red and pale blue. Electrostatic potential comparisons among HLA-DR molecules were performed in a pairwise, all-versus-all, fashion (see Online Methods) to produce distance matrices that are displayed as symmetrical heatmaps (scale ranges from 0 [identical] to 1 [maximum difference]). (a) The electrostatic potential in seven regions within the peptide binding groove (see Online Methods and Supplementary Fig. 10), which interact with the presented peptide, were compared among the HLA-DR alleles and pooled onto a single Euclidian distance matrix. The distance-based clustering identifies four clusters, with an enrichment of risk alleles in two of these. Comparison of the electrostatic potential at individual peptide binding groove regions is shown in Supplementary Fig. 13. (b) Heatmap representing electrostatic potential differences among the HLA-DR alleles at a spherical region that encompasses amino acid residues 67, 70 and 71 of the HLA-DRβ chain (associated with risk for UC and CD; Supplementary Table 13). The distance-based clustering identifies two clusters that correlate with directionality of effect in IBD.

Mentions: Given that classical HLA alleles consist of combinations of specific amino acids at multiple positions, we tested whether the association to disease could be better explained by single amino acid positions. Indeed we observed very strong association signals at many single amino acid variants in CD (e.g. five amino acids of HLA-DRβ at positions 67, 70 and 71) and in UC (e.g. 4 amino acid variants of HLA-DQα at positions 50 and 53 and 215 and 4 amino acid variants in HLA-DRβ at positions 98 and 104) and also performed per position omnibus analyses that confirm the predominant association to HLA-DRβ position 11 in UC, as previously reported 5, and to HLA-DRβ position 70 in CD (Supplementary Tables 4–5 and Supplementary Fig. 4). While the hypothesis of a positional effect is appealing, the interpretation of these position-based tests is not straightforward in the context of likely multiple causal alleles (Supplementary Note on amino acids, Supplementary Table 6 and Supplementary Fig. 5). Furthermore in this study the amino acid-based models did not capture the association at HLA-DRB1 in a more parsimonious way than the HLA allele-based models (Supplementary Note on amino acids). To further explore the basis for the observed HLA associations, we performed three-dimensional protein structure modeling followed by analysis of the electrostatic properties of the binding groove of associated (P<10−4) and common (frequency>1%) HLA-DRB1 alleles. These analyses suggest that HLA-DR alleles associated with increased risk of UC and CD, share common structural and electrostatic properties within or near their peptide binding groove that are largely distinct from those of HLA-DR alleles associated with decreased risk of UC and CD (Fig. 4).


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)

HLA-DR peptide binding groove electrostatic properties and risk of IBDThe electrostatic potential of all HLA-DR alleles associated with UC or CD, and of all common HLA-DR alleles (frequency >1%), was calculated. HLA-DR alleles associated with increased or decreased risk of IBD at study wide-significance level (P< 5×10−6) are shown in dark red or dark blue, respectively. Respective risk associations at suggestive level (1×10−4<P<5×10−6) are shown in pale red and pale blue. Electrostatic potential comparisons among HLA-DR molecules were performed in a pairwise, all-versus-all, fashion (see Online Methods) to produce distance matrices that are displayed as symmetrical heatmaps (scale ranges from 0 [identical] to 1 [maximum difference]). (a) The electrostatic potential in seven regions within the peptide binding groove (see Online Methods and Supplementary Fig. 10), which interact with the presented peptide, were compared among the HLA-DR alleles and pooled onto a single Euclidian distance matrix. The distance-based clustering identifies four clusters, with an enrichment of risk alleles in two of these. Comparison of the electrostatic potential at individual peptide binding groove regions is shown in Supplementary Fig. 13. (b) Heatmap representing electrostatic potential differences among the HLA-DR alleles at a spherical region that encompasses amino acid residues 67, 70 and 71 of the HLA-DRβ chain (associated with risk for UC and CD; Supplementary Table 13). The distance-based clustering identifies two clusters that correlate with directionality of effect in IBD.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4310771&req=5

Figure 4: HLA-DR peptide binding groove electrostatic properties and risk of IBDThe electrostatic potential of all HLA-DR alleles associated with UC or CD, and of all common HLA-DR alleles (frequency >1%), was calculated. HLA-DR alleles associated with increased or decreased risk of IBD at study wide-significance level (P< 5×10−6) are shown in dark red or dark blue, respectively. Respective risk associations at suggestive level (1×10−4<P<5×10−6) are shown in pale red and pale blue. Electrostatic potential comparisons among HLA-DR molecules were performed in a pairwise, all-versus-all, fashion (see Online Methods) to produce distance matrices that are displayed as symmetrical heatmaps (scale ranges from 0 [identical] to 1 [maximum difference]). (a) The electrostatic potential in seven regions within the peptide binding groove (see Online Methods and Supplementary Fig. 10), which interact with the presented peptide, were compared among the HLA-DR alleles and pooled onto a single Euclidian distance matrix. The distance-based clustering identifies four clusters, with an enrichment of risk alleles in two of these. Comparison of the electrostatic potential at individual peptide binding groove regions is shown in Supplementary Fig. 13. (b) Heatmap representing electrostatic potential differences among the HLA-DR alleles at a spherical region that encompasses amino acid residues 67, 70 and 71 of the HLA-DRβ chain (associated with risk for UC and CD; Supplementary Table 13). The distance-based clustering identifies two clusters that correlate with directionality of effect in IBD.
Mentions: Given that classical HLA alleles consist of combinations of specific amino acids at multiple positions, we tested whether the association to disease could be better explained by single amino acid positions. Indeed we observed very strong association signals at many single amino acid variants in CD (e.g. five amino acids of HLA-DRβ at positions 67, 70 and 71) and in UC (e.g. 4 amino acid variants of HLA-DQα at positions 50 and 53 and 215 and 4 amino acid variants in HLA-DRβ at positions 98 and 104) and also performed per position omnibus analyses that confirm the predominant association to HLA-DRβ position 11 in UC, as previously reported 5, and to HLA-DRβ position 70 in CD (Supplementary Tables 4–5 and Supplementary Fig. 4). While the hypothesis of a positional effect is appealing, the interpretation of these position-based tests is not straightforward in the context of likely multiple causal alleles (Supplementary Note on amino acids, Supplementary Table 6 and Supplementary Fig. 5). Furthermore in this study the amino acid-based models did not capture the association at HLA-DRB1 in a more parsimonious way than the HLA allele-based models (Supplementary Note on amino acids). To further explore the basis for the observed HLA associations, we performed three-dimensional protein structure modeling followed by analysis of the electrostatic properties of the binding groove of associated (P<10−4) and common (frequency>1%) HLA-DRB1 alleles. These analyses suggest that HLA-DR alleles associated with increased risk of UC and CD, share common structural and electrostatic properties within or near their peptide binding groove that are largely distinct from those of HLA-DR alleles associated with decreased risk of UC and CD (Fig. 4).

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