Skip to main content

Advertisement

Log in

Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Tuberculosis (TB) is a global public health problem and a source of preventable deaths each year, with 8.8 million new cases of TB and 1.6 million deaths worldwide in 2005. Approximately, 10% of infected individuals develop pulmonary or extrapulmonary TB, suggesting that host defense factors influence development of active disease. Toll-like receptor’ (TLR) polymorphisms have been associated with regulation of TLR expression and development of active TB. In the present study, 71 polymorphisms in TLR1, TLR2, TLR4, TLR6, and TLR9 were examined from 474 (295 cases and 179 controls) African-Americans, 381 (237 cases and 144 controls) Caucasians, and from 667 (321 cases and 346 controls) Africans from Guinea-Bissau for association with pulmonary TB using generalized estimating equations and logistic regression. Statistically significant associations were observed across populations at TLR9 and TLR2. The strongest evidence for association came at an insertion (I)/deletion (D) polymorphism (−196 to −174) in TLR2 that associated with TB in both Caucasians (II vs. ID&DD, OR = 0.41 [95% CI 0.24–0.68], p = 0.0007) and Africans (II vs. ID&DD, OR = 0.70 [95% CI 0.51–0.95], p = 0.023). Our findings in three independent population samples indicate that variations in TLR2 and TLR9 might play important roles in determining susceptibility to TB.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abecasis GR, Cookson WO (2000) GOLD—graphical overview of linkage disequilibrium. Bioinformatics 16:182–183

    Article  CAS  PubMed  Google Scholar 

  • Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2:675–680

    Article  CAS  PubMed  Google Scholar 

  • Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801

    Article  CAS  PubMed  Google Scholar 

  • Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, Du X, Hoebe K (2006) Genetic analysis of host resistance: toll-like receptor signaling and immunity at large. Annu Rev Immunol 24:353–389

    Article  CAS  PubMed  Google Scholar 

  • Bowdish DM, Sakamoto K, Kim MJ, Kroos M, Mukhopadhyay S, Leifer CA, Tryggvason K, Gordon S, Russell DG (2009) MARCO, TLR2, and CD14 are required for macrophage cytokine responses to mycobacterial trehalose dimycolate and Mycobacterium tuberculosis. PLoS Pathog 5:e1000474

    Article  PubMed  CAS  Google Scholar 

  • Branger J, Leemans JC, Florquin S, Weijer S, Speelman P, Van Der PT (2004) Toll-like receptor 4 plays a protective role in pulmonary tuberculosis in mice. Int Immunol 16:509–516

    Article  CAS  PubMed  Google Scholar 

  • Buwitt-Beckmann U, Heine H, Wiesmuller KH, Jung G, Brock R, Akira S, Ulmer AJ (2005) Toll-like receptor 6-independent signaling by diacylated lipopeptides. Eur J Immunol 35:282–289

    Article  CAS  PubMed  Google Scholar 

  • Buwitt-Beckmann U, Heine H, Wiesmuller KH, Jung G, Brock R, Akira S, Ulmer AJ (2006) TLR1- and TLR6-independent recognition of bacterial lipopeptides. J Biol Chem 281:9049–9057

    Article  CAS  PubMed  Google Scholar 

  • Comstock G (1978) Tuberculosis in twins: a re-analysis of the Prophit survey. Am Rev Respir Dis 117:621–624

    CAS  PubMed  Google Scholar 

  • Flynn JL, Goldstein MM, Chan J, Triebold KJ, Pfeffer K, Lowenstein CJ, Schreiber R, Mak TW, Bloom BR (1995) Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 2:561–572

    Article  CAS  PubMed  Google Scholar 

  • Fremond CM, Yeremeev V, Nicolle DM, Jacobs M, Quesniaux VF, Ryffel B (2004) Fatal Mycobacterium tuberculosis infection despite adaptive immune response in the absence of MyD88. J Clin Invest 114:1790–1799

    CAS  PubMed  Google Scholar 

  • Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

    Article  CAS  PubMed  Google Scholar 

  • Greenwood CMT, Fujiwara M, Boothroyd LJ, Miller MA, Frappier D, Fanning EA, Schurr E, Morgan K (2000) Linkage of tuberculosis to chromosome 2q35 loci, including NRAMP1, in a large aboriginal Canadian family. Am J Hum Genet 67:405–416

    Article  CAS  PubMed  Google Scholar 

  • Hancock DB, Martin ER, Li YJ, Scott WK (2007) Methods for interaction analyses using family-based case–control data: conditional logistic regression versus generalized estimating equations. Genet Epidemiol 31:883–893

    Article  PubMed  Google Scholar 

  • Hill PC, Brookes RH, Fox A, Fielding K, Jeffries DJ, Jackson-Sillah D, Lugos MD, Owiafe PK, Donkor SA, Hammond AS, Otu JK, Corrah T, Adegbola RA, McAdam KP (2004) Large-scale evaluation of enzyme-linked immunospot assay and skin test for diagnosis of Mycobacterium tuberculosis infection against a gradient of exposure in The Gambia. Clin Infect Dis 38:966–973

    Article  CAS  PubMed  Google Scholar 

  • Huang LY, Ishii KJ, Akira S, Aliberti J, Golding B (2005) Th1-like cytokine induction by heat-killed Brucella abortus is dependent on triggering of TLR9. J Immunol 175:3964–3970

    CAS  PubMed  Google Scholar 

  • Ma X, Liu Y, Gowen BB, Graviss EA, Clark AG, Musser JM (2007) Full-exon resequencing reveals toll-like receptor variants contribute to human susceptibility to tuberculosis disease. PLoS ONE 2:e1318

    Article  PubMed  CAS  Google Scholar 

  • Misch EA, Hawn TR (2008) Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci (Lond) 114:347–360

    Article  Google Scholar 

  • Morr M, Takeuchi O, Akira S, Simon MM, Muhlradt PF (2002) Differential recognition of structural details of bacterial lipopeptides by toll-like receptors. Eur J Immunol 32:3337–3347

    CAS  PubMed  Google Scholar 

  • Newport MJ, Allen A, Awomoyi AA, Dunstan SJ, McKinney E, Marchant A, Sirugo G (2004) The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia. Tuberculosis (Edinb) 84:347–352

    Article  CAS  Google Scholar 

  • Noguchi E, Nishimura F, Fukai H, Kim J, Ichikawa K, Shibasaki M, Arinami T (2004) An association study of asthma and total serum immunoglobin E levels for Toll-like receptor polymorphisms in a Japanese population. Clin Exp Allergy 34:177–183

    Article  CAS  PubMed  Google Scholar 

  • Okusawa T, Fujita M, Nakamura J, Into T, Yasuda M, Yoshimura A, Hara Y, Hasebe A, Golenbock DT, Morita M, Kuroki Y, Ogawa T, Shibata K (2004) Relationship between structures and biological activities of mycoplasmal diacylated lipopeptides and their recognition by toll-like receptors 2 and 6. Infect Immun 72:1657–1665

    Article  CAS  PubMed  Google Scholar 

  • Olesen R, Wejse C, Velez DR, Bisseye C, Sodemann M, Aaby P, Rabna P, Worwui A, Chapman H, Diatta M, Adegbola RA, Hill PC, Ostergaard L, Williams SM, Sirugo G (2007) DC-SIGN (CD209), pentraxin 3 and vitamin D receptor gene variants associate with pulmonary tuberculosis risk in West Africans. Genes Immun 8:456–467

    Article  CAS  PubMed  Google Scholar 

  • Skamene E, Schurr E, Gros P (1998) Infection Genomics: Nramp1 as major determinant of natural resistance to intracellular infections. Annu Rev Med 49:275–287

    Article  CAS  PubMed  Google Scholar 

  • Sousa AO, Salem JI, Lee FK, Vercosa MC, Cruaud P, Bloom BR, Lagrange PH, Hugo DL (1997) An epidemic of tuberculosis with a high rate of tuberculin anergy among a population previously unexposed to tuberculosis, the Yanomami Indians of the Brazilian Amazon. Proc Natl Acad Sci USA 94:13227–13232

    Article  CAS  PubMed  Google Scholar 

  • StataCorp (2008) Stata Statistical Software: Release 9

  • Suzuki Y, Wakita D, Chamoto K, Narita Y, Tsuji T, Takeshima T, Gyobu H, Kawarada Y, Kondo S, Akira S, Katoh H, Ikeda H, Nishimura T (2004) Liposome-encapsulated CpG oligodeoxynucleotides as a potent adjuvant for inducing type 1 innate immunity. Cancer Res 64:8754–8760

    Article  CAS  PubMed  Google Scholar 

  • Takeda K, Kaisho T, Akira S (2003) Toll-like receptors. Annu Rev Immunol 21:335–376

    Article  CAS  PubMed  Google Scholar 

  • Takeshita F, Leifer CA, Gursel I, Ishii KJ, Takeshita S, Gursel M, Klinman DM (2001) Cutting edge: Role of Toll-like receptor 9 in CpG DNA-induced activation of human cells. J Immunol 167:3555–3558

    CAS  PubMed  Google Scholar 

  • The International HapMap Consortium (2003) The International HapMap Project. Nature 426:789–796

    Article  CAS  Google Scholar 

  • Velez, Hulme WF, Weinberg FB, Levesque M, Abbato E, Estevan R, Patillow SG, Gilbert JR, Hamilton CD, Scott WK (2009) Association of SLC11A1 and pulmonary tuberculosis and interactions with NOS2A/TLR2 in African-Americans and Caucasians (submitted)

  • Wang F, Tahara T, Arisawa T, Shibata T, Nakamura M, Fujita H, Iwata M, Kamiya Y, Nagasaka M, Takahama K, Watanabe M, Hirata I, Nakano H (2007) Genetic polymorphisms of CD14 and Toll-like receptor-2 (TLR2) in patients with ulcerative colitis. J Gastroenterol Hepatol 22:925–929

    Article  CAS  PubMed  Google Scholar 

  • WHO Website (2008) World Health Organization. Programs and projects. Tuberculosis. The Stop TB Strategy

  • World Health Organization (2004) Tuberculosis. Fact Sheet Number 104, Revised March 2004 edition

Download references

Acknowledgments

The work in this manuscript was supported by grant R01 HL068534 from the National Heart, Lung and Blood Institute. C. Hamilton acknowledges support from NIH K24-AI001833. We thank the study participants, without whom this study would have been impossible, the North Carolina TB Control Nurse Consultants (Myra Allen, Dee Foster, Julie Luffman and Elizabeth Zeringue) and county TB nurses who referred subjects to the study. We would also like to thank Martha Fletcher, Elizabeth Levine, Earline Little, and Carol Poszik for assistance in recruiting participants in South Carolina, and Courtney Linton, Regina Carney, and Ann Mosher for recruiting participants in North Carolina. The Guinea Bissau study was funded by the MRC award G0000690 to G. Sirugo, and by Grants from the Danish Medical Research Council, the Danish society of respiratory medicine, the Danish Council of Development Research to C. Wejse and R. Olesen. Integrity of research and reporting: This submitted manuscript contains experiments that comply with the current laws of the country in which they were performed.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to William K. Scott.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 546 kb)

Supplementary material 2 (DOC 140 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Velez, D.R., Wejse, C., Stryjewski, M.E. et al. Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans. Hum Genet 127, 65–73 (2010). https://doi.org/10.1007/s00439-009-0741-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-009-0741-7

Keywords

Navigation