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Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis

Nature Genetics volume 44, pages 291–296 (2012)Cite this article

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Abstract

The genetic association of the major histocompatibility complex (MHC) to rheumatoid arthritis risk has commonly been attributed to alleles in HLA-DRB1. However, debate persists about the identity of the causal variants in HLA-DRB1 and the presence of independent effects elsewhere in the MHC. Using existing genome-wide SNP data in 5,018 individuals with seropositive rheumatoid arthritis (cases) and 14,974 unaffected controls, we imputed and tested classical alleles and amino acid polymorphisms in HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1 and HLA-DRB1, as well as 3,117 SNPs across the MHC. Conditional and haplotype analyses identified that three amino acid positions (11, 71 and 74) in HLA-DRβ1 and single–amino-acid polymorphisms in HLA-B (at position 9) and HLA-DPβ1 (at position 9), which are all located in peptide-binding grooves, almost completely explain the MHC association to rheumatoid arthritis risk. This study shows how imputation of functional variation from large reference panels can help fine map association signals in the MHC.

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Figure 1: Association tests within the MHC to rheumatoid arthritis.
Figure 2: Association results for amino acids in HLA-DRβ1.
Figure 3: Effects of individual amino acids within HLA proteins.
Figure 4: Three-dimensional ribbon models for the HLA-DR, HLA-B and HLA-DP proteins.
Figure 5: Conditional haplotype analysis.

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Acknowledgements

We thank the Type 1 Diabetes Genetics Consortium and the Wellcome Trust Case Control Consortium for data access. We acknowledge use of the HLA genotyping data performed by the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory on the British 1958 Birth Cohort DNA collection. This project is supported by grants from the US National Institutes of Health (K08AR055688 (S.R.), R01-AR44422 (P.K.G.), R01-AR057108 and U01-GM092691 (R.M.P.)), the Korea Healthcare Technology Research and Development Project (A102065 and A111218-11-GM01 (H.-S.L. and S.-C.B.)), the Burroughs Wellcome Fund (R.M.P.), the Arthritis Foundation (S.R.) and by the Eileen Ludwig Greenland Center for Rheumatoid Arthritis (P.K.G.).

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Authors and Affiliations

  1. Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Soumya Raychaudhuri, Cynthia Sandor, Eli A Stahl, Xiaoming Jia, Robert M Plenge & Paul I W de Bakker

  2. Division of Rheumatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Soumya Raychaudhuri, Cynthia Sandor, Eli A Stahl & Robert M Plenge

  3. Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, USA

    Soumya Raychaudhuri & Cynthia Sandor

  4. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Soumya Raychaudhuri, Cynthia Sandor, Eli A Stahl, Xiaoming Jia, Robert M Plenge & Paul I W de Bakker

  5. Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, New York, USA

    Jan Freudenberg & Peter K Gregersen

  6. Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea

    Hye-Soon Lee & Sang-Cheol Bae

  7. Harvard–Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts, USA

    Xiaoming Jia

  8. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    Lars Alfredsson

  9. Department of Medicine, Rheumatology Unit, Karolinska Institutet at Karolinska University Hospital Solna, Stockholm, Sweden

    Leonid Padyukov & Lars Klareskog

  10. Arthritis Research UK Epidemiology Unit, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK

    Jane Worthington

  11. Department of Medicine, University of Toronto, Mount Sinai Hospital and University Health Network, Toronto, Ontario, Canada

    Katherine A Siminovitch

  12. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

    Paul I W de Bakker

  13. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    Paul I W de Bakker

Authors
  1. Soumya Raychaudhuri
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  2. Cynthia Sandor
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  14. Peter K Gregersen
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  15. Paul I W de Bakker
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Contributions

S.R. and P.I.W.d.B. conceptualized and coordinated the study, oversaw the statistical analyses and wrote the initial version of the manuscript. S.R., P.I.W.d.B., C.S., E.A.S., J.F. and X.J. conducted all the statistical analyses. H.-S.L., S.-C.B., L.A., L.P., L.K., J.W., K.A.S., R.M.P. and P.K.G. organized and contributed subject samples and collected genome-wide SNP data. S.-C.B., H.-S.L. and P.K.G. provided the classical HLA genotype data. All authors contributed to writing the final manuscript.

Corresponding authors

Correspondence to Soumya Raychaudhuri or Paul I W de Bakker.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Tables 1–3, 5, 6 and Supplementary Note. (PDF 1049 kb)

Supplementary Table 4

Association analysis of all MHC markers in the European RA meta-analysis. (XLS 2050 kb)

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Raychaudhuri, S., Sandor, C., Stahl, E. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 44, 291–296 (2012). https://doi.org/10.1038/ng.1076

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