title: CD209 genetic polymorphism and tuberculosis disease.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom. fredrik.vannberg@well.ox.ac.uk
authors.forename: Fredrik O
authors.initials: FO
authors.lastname: Vannberg
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chapman
authors.forename: Chiea C
authors.initials: CC
authors.lastname: Khor
authors.forename: Kerrie
authors.initials: K
authors.lastname: Tosh
authors.forename: Sian
authors.initials: S
authors.lastname: Floyd
authors.forename: Dolly
authors.initials: D
authors.lastname: Jackson-Sillah
authors.forename: Amelia
authors.initials: A
authors.lastname: Crampin
authors.forename: Lifted
authors.initials: L
authors.lastname: Sichali
authors.forename: Boubacar
authors.initials: B
authors.lastname: Bah
authors.forename: Per
authors.initials: P
authors.lastname: Gustafson
authors.forename: Peter
authors.initials: P
authors.lastname: Aaby
authors.forename: Keith P W J
authors.initials: KP
authors.lastname: McAdam
authors.forename: Oumou
authors.initials: O
authors.lastname: Bah-Sow
authors.forename: Christian
authors.initials: C
authors.lastname: Lienhardt
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sirugo
authors.forename: Paul
authors.initials: P
authors.lastname: Fine
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
mesh_terms: D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics*; D017931:DNA Primers; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D014376:Tuberculosis / Q000235:genetics*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D017931:DNA Primers; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin