Variants in toll-like receptors 2 and 9 influence susceptibility to pulmonary tuberculosis in Caucasians, African-Americans, and West Africans
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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.
KeywordsGeneralize Estimate Equation TLR9 SNPs Bandim Health Project Genotype Frequency Difference Sequenom Mass Array
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.
- 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 296:2225–2229CrossRefPubMedGoogle 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 38:966–973CrossRefPubMedGoogle 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 72:1657–1665CrossRefPubMedGoogle 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 8:456–467CrossRefPubMedGoogle 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 94:13227–13232CrossRefPubMedGoogle Scholar
- StataCorp (2008) Stata Statistical Software: Release 9Google 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)Google Scholar
- 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 22:925–929CrossRefPubMedGoogle Scholar
- WHO Website (2008) World Health Organization. Programs and projects. Tuberculosis. The Stop TB StrategyGoogle Scholar
- World Health Organization (2004) Tuberculosis. Fact Sheet Number 104, Revised March 2004 editionGoogle Scholar