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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

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) molecules1. 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 alleles2,3. 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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Figure 1: Primary univariate association analyses of Crohn's disease and ulcerative colitis.
Figure 2: Variance explained by four-digit HLA alleles in Crohn's disease and ulcerative colitis.
Figure 3: Correlated association signals at HLA alleles support potential alternate association models for both Crohn's disease and ulcerative colitis.
Figure 4: HLA-DR peptide-binding groove electrostatic properties and risk of IBD.
Figure 5: Non-additive effect models in Crohn's disease and ulcerative colitis.
Figure 6: Comparison of OR values in Crohn's disease and ulcerative colitis for HLA alleles identified from HLA-focused models.

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Acknowledgements

We would like to thank the International PSC study group (http://www.ipscsg.org/) for sharing data. We are grateful to B.A. Lie and K. Holm for helpful discussions. J.D.R. holds a Canada Research Chair, and this work was supported by a US National Institute of Diabetes and Digestive and Kidney Diseases grant (NIDDK; R01 DK064869 and U01 DK062432). The laboratory of A.F. is supported by the German Ministry of Education and Research (BMBF) grant program e:Med (sysINFLAME). A.F. receives infrastructure support from the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence 'Inflammation at Interfaces' and holds an endowment professorship (Peter Hans Hofschneider Professorship) of the Foundation for Experimental Biomedicine (Zurich, Switzerland). Grant support for T.H.K. and A.F. was received from the European Union Seventh Framework Programme (FP7/2007-2013, grant number 262055, ESGI). M.N.C. is supported by the Intramural Research Program of the US National Institutes of Health (NIH), Frederick National Laboratory, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government. J.C.B. was supported by a Wellcome Trust grant (WT098051). D.M. and V.K. are supported by the NIHR Cambridge Biomedical Research Centre. L.P.S. is supported by an NIDDK grant (U01 DK062429-14). J.A.T. is supported by the UK Medical Research Council. D.P.B.M. is supported by the Leona M. and Harry B. Helmsley Charitable Trust, the European Union (305479) and by grants from the NIDDK (U01 DK062413, P01 DK046763-19, U54 DE023789-01), the National Institute of Allergy and Infectious Diseases (NIAID; U01 AI067068) and the Agency for Healthcare Research and Quality (AHRQ; HS021747). R.H.D. holds the Inflammatory Bowel Disease Genetic Research endowed chair at the University of Pittsburgh and was supported by an NIDDK grant (U01 DK062420) and a US National Cancer Institute grant (CA141743). S.L.H. and J.R.O. would like to also acknowledge the support of the US NIH (R01 NS049477 and 1U19 A1067152) and the National Multiple Sclerosis Society (RG 2899-D11). S.L. wishes to acknowledge support from the Australian National Health and Medical Research Council (R.D. Wright Career Development Fellowship, APP1053756).

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J.D.R., M.J.D., K.V.S., V.K., T.H.K. and A.F. jointly supervised research. J.D.R., P.G., G.B., R.H.D., J.C.B., D.P.B.M., J.A.T., M.N.C., V.K. and A.F. conceived and designed the experiments. P.G., G.B., D.M. and L.J. performed statistical analysis. P.G., G.B., L.J. and E.S.G. analyzed the data. V.A., S.L.H., J.R.O., I.T., S.L. and L.P.S. contributed reagents, materials or analysis tools. P.G., G.B., E.E., H.H. and S.R. performed data quality control and imputation. J.D.R., P.G., G.B., D.M., D.P.B.M., V.K., T.H.K. and A.F. wrote the manuscript. All authors read and approved the final manuscript before submission.

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Correspondence to John D Rioux.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–13, Supplementary Tables 1, 5–7 and 10, and Supplementary Note. (PDF 11043 kb)

Supplementary Table 2: Detailed primary and conditional association analyses of study-wide significant HLA alleles in CD.

All HLA alleles showing study-wide significant association in CD (P < 5 × 10−6), the GWAS index SNP and a few additional alleles reaching significance in conditional analyses are presented. For these variants, association statistics are shown for both the primary analysis and conditional analyses on different models. Finally, this table presents pairwise conditional analyses. (XLSX 68 kb)

Supplementary Table 3: Detailed primary and conditional association analyses of study-wide significant HLA alleles in UC.

All HLA alleles showing study-wide significant association in UC (P < 5 × 10−6), the GWAS index SNP and a few additional alleles reaching significance in conditional analyses are presented. For these variants, association statistics are shown for both the primary analysis and conditional analyses on different models. Finally, this table presents pairwise conditional analyses. (XLSX 174 kb)

Supplementary Table 4: Primary univariate analysis of single–amino acid variants and omnibus association tests at amino acid positions for all HLA genes in CD and UC.

This table includes detailed association results for amino acid variants, including per-position (omnibus) analyses (Supplementary Fig. 4). See the Online Methods and Supplementary Figure 5 for interpretation of the per-position results. (XLSX 281 kb)

Supplementary Table 8: Comparison of additive and non-additive models.

Results for the additive, recessive, dominant and general effect models (additive and dominance terms) are shown for all HLA alleles identified as independent signals in our analyses (Fig. 3). (XLSX 21 kb)

Supplementary Table 10: Non-additive effect for UC in HLA-DRB1.

Non-additive effect for UC in HLA-DRB1, presented for every possible pair of common alleles (>5%). Association analysis was conducted in the subset of samples carrying the specific alleles as homozygotes or heterozygotes (Online Methods). (XLSX 16 kb)

Supplementary Table 11: Benchmarking of HLA allele imputation.

This table includes per-allele accuracy estimates for imputed alleles in Italian and Norwegian samples (Online Methods and Supplementary Table 10). (XLSX 23 kb)

Supplementary Table 12: Primary univariate association results for SNP variants.

Primary univariate association results for SNPs (genotyped and imputed), with minor allele frequency greater than 0.5% and imputation quality info score greater than 0.5. (XLSX 1228 kb)

Supplementary Table 13: Primary univariate association results for all classical HLA alleles in CD and UC.

This table includes detailed primary association results for every HLA allele included in this study, for both CD and UC. (XLSX 76 kb)

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Goyette, P., Boucher, G., Mallon, D. et al. 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. Nat Genet 47, 172–179 (2015). https://doi.org/10.1038/ng.3176

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