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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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Non-additive effect models in CD and UCEvidence for non-additive effect of common variants (frequency >5%) across the MHC tested under a general model of additive and dominance effects (Online Methods) in CD (a,b) and UC (c,d). The p-values and directionality for departure from additive effect (dominance term) are represented on the y-axis (a,c). HLA alleles and amino acids variants are in yellow and red respectively, while SNPs are represented in dark grey. Variants with non-significant (P>5×10−6) dominance term are plotted in less pronounced colors. A clear enrichment for lower risk in heterozygotes is observed in UC (c) as suggested by the large number of significant negative dominance term (lower part of the plot). This effect is absent in CD (a), or much less important. The dominance term OR is illustrated (y-axis) versus the additive term (x-axis) (b,d). Protective and risk minor alleles are shown on the left and right sides of the plot respectively. Strictly recessive or dominant variants are expected to fall on the diagonals, while strictly additive variants lay on or close to the x-axis. The y-axis is the expected position for pure over/under dominance. In UC (d), many alleles fall into the region of the plot for protective dominant, risk recessive or overdominance (blue triangle) (see Supplementary Table 9 for pairwise comparison of HLA-DRB1 alleles). These non-additive effects are observed for many variants in UC (c,d) (e.g HLA-DRB1*03:01 and HLA-DQB1*02:01) but are mostly absent in CD (a,b); notable exception being the HLA-B*08 allele (Supplementary Fig. 6).
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Figure 5: Non-additive effect models in CD and UCEvidence for non-additive effect of common variants (frequency >5%) across the MHC tested under a general model of additive and dominance effects (Online Methods) in CD (a,b) and UC (c,d). The p-values and directionality for departure from additive effect (dominance term) are represented on the y-axis (a,c). HLA alleles and amino acids variants are in yellow and red respectively, while SNPs are represented in dark grey. Variants with non-significant (P>5×10−6) dominance term are plotted in less pronounced colors. A clear enrichment for lower risk in heterozygotes is observed in UC (c) as suggested by the large number of significant negative dominance term (lower part of the plot). This effect is absent in CD (a), or much less important. The dominance term OR is illustrated (y-axis) versus the additive term (x-axis) (b,d). Protective and risk minor alleles are shown on the left and right sides of the plot respectively. Strictly recessive or dominant variants are expected to fall on the diagonals, while strictly additive variants lay on or close to the x-axis. The y-axis is the expected position for pure over/under dominance. In UC (d), many alleles fall into the region of the plot for protective dominant, risk recessive or overdominance (blue triangle) (see Supplementary Table 9 for pairwise comparison of HLA-DRB1 alleles). These non-additive effects are observed for many variants in UC (c,d) (e.g HLA-DRB1*03:01 and HLA-DQB1*02:01) but are mostly absent in CD (a,b); notable exception being the HLA-B*08 allele (Supplementary Fig. 6).

Mentions: While we performed the primary analyses based on a dose effect model, our sample size allowed us to investigate the effects further, by testing for non-additive effects. In fact we found significant departure from additive effects in UC, but not for CD (Fig 5a–c). Specifically, we found evidence of decreased heterozygosity in UC patients for genotyped and imputed variants across the MHC and at HLA genes, mostly in class II (Supplementary Tables 7–8). This heterozygote advantage could be explained by an enrichment of dominant protective and recessive risk alleles11, that is absent or much less important in CD (Fig. 5 and Supplementary Fig. 6). Notably, we also detected multiple overdominant effects in UC, the strongest of which is captured by HLA-DRB1*03:01 (Fig. 5, Supplementary Fig. 6–7, and Supplementary Table 9). This allele is mostly found on the ancestral haplotype 8.1, a relatively common (~5–10%) haplotype that is conserved in European populations and that is implicated in other immune diseases 12–14. The overdominance effect of this haplotype in UC is possibly due to the presence of both dominant protective and recessive risk alleles, which would be consistent with the reported recessive risk of this haplotype in the UC-related biliary disease primary sclerosing cholangitis (Supplementary Fig. 8–9) 15,16. Analogous with an infectious paradigm 11, these data may suggest that decreased HLA class II heterozygosity may impair the ability to appropriately control colonic microbiota in UC.


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)

Non-additive effect models in CD and UCEvidence for non-additive effect of common variants (frequency >5%) across the MHC tested under a general model of additive and dominance effects (Online Methods) in CD (a,b) and UC (c,d). The p-values and directionality for departure from additive effect (dominance term) are represented on the y-axis (a,c). HLA alleles and amino acids variants are in yellow and red respectively, while SNPs are represented in dark grey. Variants with non-significant (P>5×10−6) dominance term are plotted in less pronounced colors. A clear enrichment for lower risk in heterozygotes is observed in UC (c) as suggested by the large number of significant negative dominance term (lower part of the plot). This effect is absent in CD (a), or much less important. The dominance term OR is illustrated (y-axis) versus the additive term (x-axis) (b,d). Protective and risk minor alleles are shown on the left and right sides of the plot respectively. Strictly recessive or dominant variants are expected to fall on the diagonals, while strictly additive variants lay on or close to the x-axis. The y-axis is the expected position for pure over/under dominance. In UC (d), many alleles fall into the region of the plot for protective dominant, risk recessive or overdominance (blue triangle) (see Supplementary Table 9 for pairwise comparison of HLA-DRB1 alleles). These non-additive effects are observed for many variants in UC (c,d) (e.g HLA-DRB1*03:01 and HLA-DQB1*02:01) but are mostly absent in CD (a,b); notable exception being the HLA-B*08 allele (Supplementary Fig. 6).
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Related In: Results  -  Collection

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Figure 5: Non-additive effect models in CD and UCEvidence for non-additive effect of common variants (frequency >5%) across the MHC tested under a general model of additive and dominance effects (Online Methods) in CD (a,b) and UC (c,d). The p-values and directionality for departure from additive effect (dominance term) are represented on the y-axis (a,c). HLA alleles and amino acids variants are in yellow and red respectively, while SNPs are represented in dark grey. Variants with non-significant (P>5×10−6) dominance term are plotted in less pronounced colors. A clear enrichment for lower risk in heterozygotes is observed in UC (c) as suggested by the large number of significant negative dominance term (lower part of the plot). This effect is absent in CD (a), or much less important. The dominance term OR is illustrated (y-axis) versus the additive term (x-axis) (b,d). Protective and risk minor alleles are shown on the left and right sides of the plot respectively. Strictly recessive or dominant variants are expected to fall on the diagonals, while strictly additive variants lay on or close to the x-axis. The y-axis is the expected position for pure over/under dominance. In UC (d), many alleles fall into the region of the plot for protective dominant, risk recessive or overdominance (blue triangle) (see Supplementary Table 9 for pairwise comparison of HLA-DRB1 alleles). These non-additive effects are observed for many variants in UC (c,d) (e.g HLA-DRB1*03:01 and HLA-DQB1*02:01) but are mostly absent in CD (a,b); notable exception being the HLA-B*08 allele (Supplementary Fig. 6).
Mentions: While we performed the primary analyses based on a dose effect model, our sample size allowed us to investigate the effects further, by testing for non-additive effects. In fact we found significant departure from additive effects in UC, but not for CD (Fig 5a–c). Specifically, we found evidence of decreased heterozygosity in UC patients for genotyped and imputed variants across the MHC and at HLA genes, mostly in class II (Supplementary Tables 7–8). This heterozygote advantage could be explained by an enrichment of dominant protective and recessive risk alleles11, that is absent or much less important in CD (Fig. 5 and Supplementary Fig. 6). Notably, we also detected multiple overdominant effects in UC, the strongest of which is captured by HLA-DRB1*03:01 (Fig. 5, Supplementary Fig. 6–7, and Supplementary Table 9). This allele is mostly found on the ancestral haplotype 8.1, a relatively common (~5–10%) haplotype that is conserved in European populations and that is implicated in other immune diseases 12–14. The overdominance effect of this haplotype in UC is possibly due to the presence of both dominant protective and recessive risk alleles, which would be consistent with the reported recessive risk of this haplotype in the UC-related biliary disease primary sclerosing cholangitis (Supplementary Fig. 8–9) 15,16. Analogous with an infectious paradigm 11, these data may suggest that decreased HLA class II heterozygosity may impair the ability to appropriately control colonic microbiota in UC.

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