Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

Nature Genetics volume 47, pages 523–527 (2015)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: GWAS of susceptibility to TB.
Figure 2: ASAP1 expression in peripheral blood leukocytes and monocyte-derived macrophages and DCs.
Figure 3: In DCs, the ASAP1 protein is partly associated with podosomes, and its depletion leads to impaired matrix degradation and migration.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Zumla, A., Raviglione, M., Hafner, R. & von Reyn, C.F. Tuberculosis. N. Engl. J. Med. 368, 745–755 (2013).

    Article  CAS  Google Scholar 

  2. Möller, M. & Hoal, E.G. Current findings, challenges and novel approaches in human genetic susceptibility to tuberculosis. Tuberculosis (Edinb.) 90, 71–83 (2010).

    Article  Google Scholar 

  3. Apt, A. & Kramnik, I. Man and mouse TB: contradictions and solutions. Tuberculosis (Edinb.) 89, 195–198 (2009).

    Article  Google Scholar 

  4. Thye, T. et al. Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2. Nat. Genet. 42, 739–741 (2010).

    Article  CAS  Google Scholar 

  5. Thye, T. et al. Common variants at 11p13 are associated with susceptibility to tuberculosis. Nat. Genet. 44, 257–259 (2012).

    Article  CAS  Google Scholar 

  6. Chimusa, E.R. et al. Genome-wide association study of ancestry-specific TB risk in the South African Coloured population. Hum. Mol. Genet. 23, 796–809 (2014).

    Article  CAS  Google Scholar 

  7. Zhang, F.R. et al. Genome-wide association study of leprosy. N. Engl. J. Med. 361, 2609–2618 (2009).

    Article  CAS  Google Scholar 

  8. Zhang, F. et al. Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy. Nat. Genet. 43, 1247–1251 (2011).

    Article  CAS  Google Scholar 

  9. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    Article  CAS  Google Scholar 

  10. Nie, Z. & Randazzo, P.A. Arf GAPs and membrane traffic. J. Cell Sci. 119, 1203–1211 (2006).

    Article  CAS  Google Scholar 

  11. Randazzo, P.A., Inoue, H. & Bharti, S. Arf GAPs as regulators of the actin cytoskeleton. Biol. Cell 99, 583–600 (2007).

    Article  CAS  Google Scholar 

  12. Murphy, D.A. & Courtneidge, S.A. The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function. Nat. Rev. Mol. Cell Biol. 12, 413–426 (2011).

    Article  CAS  Google Scholar 

  13. Bharti, S. et al. Src-dependent phosphorylation of ASAP1 regulates podosomes. Mol. Cell. Biol. 27, 8271–8283 (2007).

    Article  CAS  Google Scholar 

  14. Lin, D. et al. ASAP1, a gene at 8q24, is associated with prostate cancer metastasis. Cancer Res. 68, 4352–4359 (2008).

    Article  CAS  Google Scholar 

  15. Onodera, Y. et al. Expression of AMAP1, an ArfGAP, provides novel targets to inhibit breast cancer invasive activities. EMBO J. 24, 963–973 (2005).

    Article  CAS  Google Scholar 

  16. Ehlers, J.P., Worley, L., Onken, M.D. & Harbour, J.W. DDEF1 is located in an amplified region of chromosome 8q and is overexpressed in uveal melanoma. Clin. Cancer Res. 11, 3609–3613 (2005).

    Article  CAS  Google Scholar 

  17. Müller, T. et al. ASAP1 promotes tumor cell motility and invasiveness, stimulates metastasis formation in vivo, and correlates with poor survival in colorectal cancer patients. Oncogene 29, 2393–2403 (2010).

    Article  Google Scholar 

  18. Lin, P.L. et al. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat. Med. 20, 75–79 (2014).

    Article  CAS  Google Scholar 

  19. Ernst, J.D. The immunological life cycle of tuberculosis. Nat. Rev. Immunol. 12, 581–591 (2012).

    Article  CAS  Google Scholar 

  20. Wolf, A.J. et al. Mycobacterium tuberculosis infects dendritic cells with high frequency and impairs their function in vivo. J. Immunol. 179, 2509–2519 (2007).

    Article  CAS  Google Scholar 

  21. Wolf, A.J. et al. Initiation of the adaptive immune response to Mycobacterium tuberculosis depends on antigen production in the local lymph node, not the lungs. J. Exp. Med. 205, 105–115 (2008).

    Article  CAS  Google Scholar 

  22. Roberts, L.L. & Robinson, C.M. Mycobacterium tuberculosis infection of human dendritic cells decreases integrin expression, adhesion and migration to chemokines. Immunology 141, 39–51 (2014).

    Article  CAS  Google Scholar 

  23. Barreiro, L.B. et al. Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection. Proc. Natl. Acad. Sci. USA 109, 1204–1209 (2012).

    Article  CAS  Google Scholar 

  24. Szeszko, J.S. et al. Resequencing and association analysis of the SP110 gene in adult pulmonary tuberculosis. Hum. Genet. 121, 155–160 (2007).

    Article  CAS  Google Scholar 

  25. Korn, J.M. et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat. Genet. 40, 1253–1260 (2008).

    Article  CAS  Google Scholar 

  26. Howie, B.N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

    Article  Google Scholar 

  27. Howie, B., Marchini, J. & Stephens, M. Genotype imputation with thousands of genomes. G3 1, 457–470 (2012).

    Article  Google Scholar 

  28. Marchini, J. & Howie, B. Genotype imputation for genome-wide association studies. Nat. Rev. Genet. 11, 499–511 (2010).

    CAS  Google Scholar 

  29. Maller, J.B. et al. Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat. Genet. 44, 1294–1301 (2012).

    Article  CAS  Google Scholar 

  30. Howie, B., Fuchsberger, C., Stephens, M., Marchini, J. & Abecasis, G.R. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955–959 (2012).

    Article  CAS  Google Scholar 

  31. Götz, A. & Jessberger, R. Dendritic cell podosome dynamics does not depend on the F-actin regulator SWAP-70. PLoS ONE 8, e60642 (2013).

    Article  Google Scholar 

Download references

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

  1. James Curtis, Yang Luo and Helen L Zenner: These authors contributed equally to this work.

Authors and 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

Authors
  1. James Curtis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yang Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Helen L Zenner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Delphine Cuchet-Lourenço
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Changxin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kitty Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mailis Maes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ali Alisaac
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Emma Stebbings
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jimmy Z Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Liliya Kopanitsa
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Olga Ignatyeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yanina Balabanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Vladyslav Nikolayevskyy
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ingelore Baessmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Thorsten Thye
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Christian G Meyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Peter Nürnberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Rolf D Horstmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Francis Drobniewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Vincent Plagnol
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Jeffrey C Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Sergey Nejentsev
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Sergey Nejentsev.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Quality control of the GWAS samples by heterozygosity and missing genotypes rate

Dashed red lines represent QC thresholds of more than 2% missing genotype data or excess ± 3.5 standard deviation of heterozygosity rate. Samples circled in red were excluded from the association study.

Supplementary Figure 2 Principal component analysis (PCA) of the Russian GWAS samples

(a) First and second principal components. Russian samples are plotted with ten HapMap3 populations (ASW – African ancestry in Southwest USA; CEU – Utah residents of European ancestry; CHB – Han Chinese in Beijing, China; CHD – Chinese in Metropolitan Denver, Colorado; JPT – Japanese in Tokyo, Japan; GIH – Gujarati Indians in Houston, Texas; LWK – Luhya in Webuye, Kenya; MKK – Maasai in Kinyawa, Kenya; TSI – Tuscans in Italy; YRI – Yoruba in Ibadan, Nigeria).

(b) All GWAS samples plotted on the first two principal components colored by the city of sample origin.

(c) Russian TB cases and controls projected onto the first two principal components using SNP weights precomputed from European samples in the 1000 Genomes Phase III project (CEU — Utah residents with Northern and Western European ancestry; IBS — Iberian populations in Spain; FIN — Finnish in Finland; GBR — British in England and Scotland; and TSI — Toscani in Italy) using SNPweights (Chen, C.Y. et al. Improved ancestry inference using weights from external reference panels. Bioinformatics 29, 1399-1406 (2013)).

Supplementary Figure 3 The quantile - quantile plot of the observed versus the expected –log10P-values under the null for 7,614,862 SNPs from the GWAS results after genotype imputation

The diagonal black line is y = x, and the grey shapes show 95% confidence interval under the null. The overall distribution has a genomic inflation factor (λGC) of 1.10.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 (PDF 391 kb)

Supplementary Tables

Supplementary Tables 1–3 and 5–7 (PDF 215 kb)

Supplementary Table 4

TB association in the Russian GWAS for loci that previously were associated with Inflammatory Bowel Disease (XLS 48 kb)

Source data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Curtis, J., Luo, Y., Zenner, H. et al. Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration. Nat Genet 47, 523–527 (2015). https://doi.org/10.1038/ng.3248

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing