Journal Article

CD209 Genetic Polymorphism and Tuberculosis Disease

Khor, Chiea C., Tosh, Kerrie, Bah, Boubacar, McAdam, Keith P. W. J., Floyd, Sian, Sichali, Lifted, Aaby, Peter, Jackson-Sillah, Dolly, Lienhardt, Christian, Fine, Paul, Hill, Adrian V. S., Sirugo, Giorgio, Bah-Sow, Oumou, Vannberg, Fredrik O., Gustafson, Per, Crampin, Amelia, Chapman, Stephen J.

2008

Overview

Tuberculosis causes significant morbidity and mortality worldwide, especially in sub-Saharan Africa. DC-SIGN, encoded by CD209, is a receptor capable of binding and internalizing Mycobacterium tuberculosis. Previous studies have reported that the CD209 promoter single nucleotide polymorphism (SNP)-336A/G exerts an effect on CD209 expression and is associated with human susceptibility to dengue, HIV-1 and tuberculosis in humans. The present study investigates the role of the CD209 -336A/G variant in susceptibility to tuberculosis in a large sample of individuals from sub-Saharan Africa. A total of 2,176 individuals enrolled in tuberculosis case-control studies from four sub-Saharan Africa countries were genotyped for the CD209 -336A/G SNP (rs4804803). Significant overall protection against pulmonary tuberculosis was observed with the -336G allele when the study groups were combined (n = 914 controls vs. 1262 cases, Mantel-Haenszel 2 x 2 chi(2) = 7.47, P = 0.006, odds ratio = 0.86, 95%CI 0.77-0.96). In addition, the patients with -336GG were associated with a decreased risk of cavitory tuberculosis, a severe form of tuberculosis disease (n = 557, Pearson's 2x2 chi(2) = 17.34, P = 0.00003, odds ratio = 0.42, 95%CI 0.27-0.65). This direction of association is opposite to a previously observed result in a smaller study of susceptibility to tuberculosis in a South African Coloured population, but entirely in keeping with the previously observed protective effect of the -336G allele. This study finds that the CD209 -336G variant allele is associated with significant protection against tuberculosis in individuals from sub-Saharan Africa and, furthermore, cases with -336GG were significantly less likely to develop tuberculosis-induced lung cavitation. Previous in vitro work demonstrated that the promoter variant -336G allele causes down-regulation of CD209 mRNA expression. Our present work suggests that decreased levels of the DC-SIGN receptor may therefore be protective against both clinical tuberculosis in general and cavitory tuberculosis disease in particular. This is consistent with evidence that Mycobacteria can utilize DC-SIGN binding to suppress the protective pro-inflammatory immune response.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alleles / Base Sequence / Binding / Binding sites / Carbohydrates / Case-Control Studies / Cavitation / Cell Adhesion Molecules - genetics / Councils / Cytokines / DC-SIGN protein / Dendritic cells / Dengue / Dengue fever / Development and progression / Disease / DNA Primers / Down-regulation / Gene expression / Gene polymorphism / Genetic aspects / Genetics / Genetics and Genomics/Genetics of the Immune System / Health aspects / HIV / Human immunodeficiency virus / Humans / Hygiene / Immune response / Immune system / Inflammation / Laboratories / Lectins / Lectins, C-Type - genetics / Leprosy / Ligands / Lungs / Mass spectrometry / Medical research / Medicine / Morbidity / Mortality / Mycobacterium tuberculosis / Pattern recognition / Polymorphism / Polymorphism, Single Nucleotide / Receptors, Cell Surface - genetics / Scientific imaging / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Streptococcus infections / Studies / Tuberculosis / Tuberculosis - genetics / Vector-borne diseases / Viral diseases