Article

DC-SIGN (CD209), Pentraxin 3 and Vitamin D Receptor gene variants associate with pulmonary tubercolosis risk in West-Africans

Vanderbilt University, Нашвилл, Michigan, United States
Genes and Immunity (Impact Factor: 2.91). 10/2007; 8(6):456-67. DOI: 10.1038/sj.gene.6364410
Source: PubMed

ABSTRACT

We investigated the role of DC-SIGN (CD209), long pentraxin 3 (PTX3) and vitamin D receptor (VDR) gene single nucleotide polymorphisms (SNPs) in susceptibility to pulmonary tuberculosis (TB) in 321 TB cases and 347 healthy controls from Guinea-Bissau. Five additional, functionally relevant SNPs within toll-like receptors (TLRs) 2, 4 and 9 were typed but found, when polymorphic, not to affect host vulnerability to pulmonary TB. We did not replicate an association between SNPs in the DC-SIGN promoter and TB. However, we found that two polymorphisms, one in DC-SIGN and one in VDR, were associated in a nonadditive model with disease risk when analyzed in combination with ethnicity (P=0.03 for DC-SIGN and P=0.003 for VDR). In addition, PTX3 haplotype frequencies significantly differed in cases compared to controls and a protective effect was found in association with a specific haplotype (OR 0.78, 95% CI 0.63-0.98). Our findings support previous data showing that VDR SNPs modulate the risk for TB in West Africans and suggest that variation within DC-SIGN and PTX3 also affect the disease outcome.

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    • "Mechanistically, PTX3 acts as an opsonin, which not only enhances phagocytosis and killing of pathogens but also promotes dendritic cell maturation and polarization, thereby contributing to the activation of the adaptive immune response (Bottazzi et al., 2010). Intriguingly, polymorphisms in the PTX3 gene are associated with risk for pulmonary tuberculosis and P. aeruginosa infections in cystic fibrosis (Olesen et al., 2007; Chiarini et al., 2010). Furthermore, PTX3 mediates a variety of antiviral activities against influenza viruses, including inhibition of virus-induced hemagglutination and viral neuramidase activity, as well as neutralization of virus infectivity in vitro (Reading et al., 2008). "
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    • "The distribution of PTX3 plasma levelsthat the carriers of the AA genotype at the rs2305619 SNP had the higher amount of PTX3 in the blood compared to the AG and GG carriers, while GG genotyping is associated with the lower value of plasma PTX3. These results are matched with the study of Barbati et al.[24]who stated that carriers for AA rs2305619 (vs.AG and GG genotypes) had higher PTX3 levels, while GG genotyping has been previously associated with a protective effect against pulmonary tuberculosis in West Africans[40]and Pseudomonas aeruginosa colonization in Italian cystic fibrosis patients[41]. The mechanism by which PTX3 SNPs affect PTX3 plasma levels is still to be clarified but possibly the rs2305619 genetic variant is in linkage with a regulatory region, perhaps the PTX3 promoter. "
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    • "These findings have motivated a large number of linkage and candidate gene association studies seeking to identify relevant susceptibility loci, but results have often been inconclusive or, worse, contradictory. Many biologically plausible genes, such as those that encode vitamin-D-binding protein (Lewis et al., 2005; Gao et al., 2010), the phagolysomal membrane protein NRAMP/SLC11A1 (Hoal et al., 2004; Velez et al., 2009), and the dendritic adhesion molecule DC-SIGN (Barreiro et al., 2006; Olesen et al., 2007), appear to associate with TB in some human populations, but not others. Inconsistent replication across ethnic groups has also beset the handful of GWAS performed on TB (Chimusa et al., 2014). "
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