Abstract

Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found an association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 (P = 2.6 × 10−11 for rs4733781; P = 1.0 × 10−10 for rs10956514). Dendritic cells (DCs) showed high ASAP1 expression that was reduced after Mycobacterium tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in M. tuberculosis–infected DCs may lead to their impaired migration, suggesting a potential mechanism of predisposition to TB.

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Acknowledgements

The study was supported by Wellcome Trust grants 088838/Z/09/Z (to S.N., J.C.B., F.D.) and 095198/Z/10/Z (to S.N.), EU Framework Programme 7 Collaborative grant 201483 (to S.N., F.D., R.D.H., P.N.), European Research Council Starting grant 260477 (to S.N.), and Royal Society grants UF0763346 (to S.N.) and RG090638 (to S.N.). S.N. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science and is also supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113, 085475 and 090355.

Author information

Author notes

    • James Curtis
    • , Yang Luo
    •  & Helen L Zenner

    These authors contributed equally to this work.

Affiliations

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

    • James Curtis
    • , Helen L Zenner
    • , Delphine Cuchet-Lourenço
    • , Changxin Wu
    • , Mailis Maes
    • , Ali Alisaac
    • , Emma Stebbings
    • , Liliya Kopanitsa
    •  & Sergey Nejentsev
  2. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Yang Luo
    • , Jimmy Z Liu
    •  & Jeffrey C Barrett
  3. University College London Genetics Institute, University College London, London, UK.

    • Kitty Lo
    •  & Vincent Plagnol
  4. Samara Oblast Tuberculosis Dispensary, Samara, Russia.

    • Olga Ignatyeva
  5. Robert Koch Institute, Berlin, Germany.

    • Yanina Balabanova
  6. Imperial College London, London, UK.

    • Yanina Balabanova
    • , Vladyslav Nikolayevskyy
    •  & Francis Drobniewski
  7. Queen Mary University of London, London, UK.

    • Yanina Balabanova
    • , Vladyslav Nikolayevskyy
    •  & Francis Drobniewski
  8. Public Health England National Mycobacterium Reference Laboratory, London, UK.

    • Vladyslav Nikolayevskyy
    •  & Francis Drobniewski
  9. Cologne Center for Genomics, University of Cologne, Cologne, Germany.

    • Ingelore Baessmann
    •  & Peter Nürnberg
  10. Department of Molecular Medicine, Bernhard Nocht Institute for Topical Medicine, Hamburg, Germany.

    • Thorsten Thye
    • , Christian G Meyer
    •  & Rolf D Horstmann
  11. Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.

    • Peter Nürnberg
  12. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.

    • Peter Nürnberg

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Contributions

S.N. conceived and supervised the study, participated in sample collection and data analysis, and wrote the first draft of the manuscript. J.C. prepared DNA samples and participated in their genotyping and analysis. Y.L. performed statistical analysis of the GWAS data. J.Z.L. participated in the GWAS data analysis. H.L.Z. and D.C.-L. studied DCs and performed matrix degradation and cell migration experiments. C.W. studied ASAP1 mRNA expression in leukocytes. K.L. performed expression quantitative trait locus (eQTL) analysis in DCs. M.M. and A.A. prepared cells for functional experiments. O.I., Y.B., V.N., R.D.H. and F.D. participated in study design, protocol development and sample collection. E.S. and L.K. participated in DNA sample extraction. I.B. and P.N. participated in genotyping. T.T. and C.G.M. participated in genotyping and analysis of the Ghanaian data. V.P. and J.C.B. participated in and supervised statistical analyses. All authors contributed to the writing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sergey Nejentsev.

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    Supplementary Table 4

    TB association in the Russian GWAS for loci that previously were associated with Inflammatory Bowel Disease

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DOI

https://doi.org/10.1038/ng.3248

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