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HLA class II sequence variants influence tuberculosis risk in populations of European ancestry

Nature Genetics volume 48, pages 318–322 (2016)Cite this article

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Abstract

Mycobacterium tuberculosis infections cause 9 million new tuberculosis cases and 1.5 million deaths annually1. To identify variants conferring risk of tuberculosis, we tested 28.3 million variants identified through whole-genome sequencing of 2,636 Icelanders for association with tuberculosis (8,162 cases and 277,643 controls), pulmonary tuberculosis (PTB) and M. tuberculosis infection. We found association of three variants in the region harboring genes encoding the class II human leukocyte antigens (HLAs): rs557011[T] (minor allele frequency (MAF) = 40.2%), associated with M. tuberculosis infection (odds ratio (OR) = 1.14, P = 3.1 × 10−13) and PTB (OR = 1.25, P = 5.8 × 10−12), and rs9271378[G] (MAF = 32.5%), associated with PTB (OR = 0.78, P = 2.5 × 10−12)—both located between HLA-DQA1 and HLA-DRB1—and a missense variant encoding p.Ala210Thr in HLA-DQA1 (MAF = 19.1%, rs9272785), associated with M. tuberculosis infection (P = 9.3 × 10−9, OR = 1.14). We replicated association of these variants with PTB in samples of European ancestry from Russia and Croatia (P < 5.9 × 10−4). These findings show that the HLA class II region contributes to genetic risk of tuberculosis, possibly through reduced presentation of protective M. tuberculosis antigens to T cells.

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Figure 1: Regional association plot of the HLA 6p21 locus for PTB (n = 3,686), all TB (n = 8,162) and M. tuberculosis infection with or without TB (n = 14,723).

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Acknowledgements

The authors thank the study participants and the staff at the Patient Recruitment Center and the deCODE genetics core facilities. We thank S. Balen (University of Rijeka) and M. Balija (Croatian Institute for Transfusion Medicine) for assistance in the collection of blood samples, S. Grle-Popovic for assistance in collection of blood samples of tuberculosis patients treated at the University Hospital Center, Zagreb, and J. Pavelic (Ruđer Bošković Institute) for providing resources and advice. This work was supported by the US National Institute of Allergy and Infectious Diseases grant HHSN266200400064C (deCODE Genetics, A. Kong, K.G.K., M.G., M.K.), UK Wellcome Trust grants 088838/Z/09/Z and 095198/Z/10/Z (S.N.), EU Framework Programme 7 Collaborative grant 201483 (University of Cambridge and S.N.), European Research Council Starting grant 260477 and Royal Society grants UF0763346 and RG090638 (S.N.). S.N. is also supported by a Wellcome Trust Senior Research fellowship and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.

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Authors and Affiliations

  1. deCODE genetics/Amgen Inc., Reykjavik, Iceland

    Gardar Sveinbjornsson, Daniel F Gudbjartsson, Bjarni V Halldorsson, Larus J Gudmundsson, Arnaldur Gylfason, Sigurjon Axel Gudjonsson, Hafdis T Helgadottir, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Ari Karason, Helgi Kristjansson, Olafur T Magnusson, Patrick Sulem, Augustine Kong, Gisli Masson, Unnur Thorsteinsdottir, Ingileif Jonsdottir & Kari Stefansson

  2. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland

    Gardar Sveinbjornsson & Daniel F Gudbjartsson

  3. School of Science and Engineering, Reykjavik University, Reykjavik, Iceland

    Bjarni V Halldorsson

  4. Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland

    Karl G Kristinsson, Magnus Gottfredsson, Helgi Kristjansson, Arthur Love, Unnur Thorsteinsdottir, Ingileif Jonsdottir & Kari Stefansson

  5. Department of Clinical Microbiology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland

    Karl G Kristinsson

  6. Department of Infectious Diseases, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland

    Magnus Gottfredsson & Mar Kristjansson

  7. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK

    Jeffrey C Barrett & Yang Luo

  8. Division of Communicable Disease Prevention and Control, Primary Health Care of the Capital Area, Reykjavik, Iceland

    Kai Blondal & Thorsteinn Blondal

  9. Department of Pulmonology, Clinic of Internal Medicine, Clinical Hospital Center, University of Rijeka, Rijeka, Croatia

    Ljiljana Bulat Kardum

  10. Department of Oral Biology, Laboratory of Molecular Genetics, Faculty of Dentistry, University of Oslo, Oslo, Norway

    Jelena Knežević & Zlatko Dembic

  11. Division of Molecular Medicine, Ruđer Boškovic´ Institute, Zagreb, Croatia

    Jelena Knežević

  12. Department of Virology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland

    Arthur Love

  13. Department of Medicine, University of Cambridge, Cambridge, UK

    Sergey Nejentsev

  14. Department of Immunology, Landspitali, the National University Hospital of Iceland, Reykjavik, Iceland

    Ingileif Jonsdottir

Authors
  1. Gardar Sveinbjornsson
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  2. Daniel F Gudbjartsson
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  30. Kari Stefansson
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Contributions

G.S., D.F.G., B.V.H., A. Kong, U.T., T.B., I.J. and K.S. designed the study and interpreted the results. T.B., K.G.K., M.G., L.J.G., A.L., M.K. and K.B. coordinated and managed phenotype data ascertainment and Icelandic subject recruitment. S.N., J.C.B. and Y.L. coordinated, managed, genotyped and analyzed the Russian cohort sample set. L.B.K., J.K. and Z.D. coordinated and managed the Croatian cohort phenotypes and samples, which were genotyped and analyzed by deCODE. G.S., H.T.H., G.M., S.A.G., O.T.M., U.T. and I.J. performed the sequencing, genotyping and expression analyses. G.S., D.F.G., B.V.H., S.A.G., A.G., Adalbjorg Jonasdottir, Aslaug Jonasdottir, A. Karason, H.K. and I.J. performed HLA typing and analysis of HLA data. G.S., D.F.G., B.V.H., A.G., S.A.G., P.S., A. Kong, G.M. and I.J. performed the statistical and bioinformatics analyses. G.S., D.F.G., S.N., I.J. and K.S. drafted the manuscript. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Ingileif Jonsdottir or Kari Stefansson.

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Competing interests

G.S., D.F.G., B.V.H., L.J.G., A.G., S.A.G., H.T.H., Adalbjorg Jonasdottir, Aslaug Jonasdottir, A. Karason, H.K., O.T.M., P.S., A. Kong, G.M., U.T., I.J. and K.S. are employed by deCODE Genetics/Amgen, Inc.

Integrated supplementary information

Supplementary Figure 1 Q-Q plots of tuberculosis GWAS results.

Q-Q plots using uncorrected (red) and corrected (blue, using the method of genomic control) χ2 statistics from the tuberculosis GWAS of pulmonary tuberculosis, all tuberculosis and M. tuberculosis. All P-values below 0.05 are plotted.

Supplementary Figure 2 Principal components plot of cases and controls.

The figure shows first two principal components of the Icelandic cases and controls used in the association. Pulmonary tuberculosis, all tuberculosis and M. tuberculosis infected cases are plotted in blue, and population controls in black.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2, Supplementary Tables 1–6 and 8–12, and Supplementary Note (PDF 1644 kb)

Supplementary Table 7

Association signals of imputed classical HLA alleles with PTB in Iceland. HLA alleles at four digit levels were established using imputation of sequence data from a set of 2,614 whole-genome sequenced individuals (XLSX 38 kb)

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Sveinbjornsson, G., Gudbjartsson, D., Halldorsson, B. et al. HLA class II sequence variants influence tuberculosis risk in populations of European ancestry. Nat Genet 48, 318–322 (2016). https://doi.org/10.1038/ng.3498

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