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