CD209 genetic polymorphism and tuberculosis disease |
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Authors: | Vannberg Fredrik O Chapman Stephen J Khor Chiea C Tosh Kerrie Floyd Sian Jackson-Sillah Dolly Crampin Amelia Sichali Lifted Bah Boubacar Gustafson Per Aaby Peter McAdam Keith P W J Bah-Sow Oumou Lienhardt Christian Sirugo Giorgio Fine Paul Hill Adrian V S |
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Institution: | Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. fredrik.vannberg@well.ox.ac.uk |
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Abstract: | BackgroundTuberculosis 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.Methods and FindingsA 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 2x2 χ2?=?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 2×2 χ2?=?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.ConclusionThis 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. |
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