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

MRC Laboratories, Banjul, The Gambia.
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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Available from: Christian Wejse, Sep 27, 2015
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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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    ABSTRACT: A major goal in infectious disease research is to identify the human and pathogenic genetic variants that explain differences in microbial pathogenesis. However, neither pathogenic strain nor human genetic variation in isolation has proven adequate to explain the heterogeneity of disease pathology. We suggest that disrupted co-evolution between a pathogen and its human host can explain variation in disease outcomes, and that genome-by-genome interactions should therefore be incorporated into genetic models of disease caused by infectious agents. Genetic epidemiological studies that fail to take both the pathogen and host into account can lead to false and misleading conclusions about disease etiology. We discuss our model in the context of three pathogens, Helicobacter pylori, Mycobacterium tuberculosis and human papillomavirus, and generalize the conditions under which it may be applicable.
    Frontiers in Genetics 08/2014; 5:290. DOI:10.3389/fgene.2014.00290
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    • "The pulmonary TB data is from a case-control study [30] conducted at The Bandim Health Project (BHP) in Bissau , the capital city of Guinea-Bissau. This area has a high prevalence of pulmonary TB and TB symptoms [4]. "
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    ABSTRACT: We analyzed two West African samples (Guinea-Bissau: n=289 cases and 322 controls; The Gambia: n=240 cases and 248 controls) to evaluate single-nucleotide polymorphisms (SNPs) in Epiregulin (EREG) and V-ATPase (T-cell immune regulator 1 (TCIRG1)) using single and multilocus analyses to determine whether previously described associations with pulmonary tuberculosis (PTB) in Vietnamese and Italians would replicate in African populations. We did not detect any significant single locus or haplotype associations in either sample. We also performed exploratory pairwise interaction analyses using Visualization of Statistical Epistasis Networks (ViSEN), a novel method to detect only interactions among multiple variables, to elucidate possible interaction effects between SNPs and demographic factors. Although we found no strong evidence of marginal effects, there were several significant pairwise interactions that were identified in either the Guinea-Bissau or the Gambian samples, two of which replicated across populations. Our results indicate that the effects of EREG and TCIRG1 variants on PTB susceptibility, to the extent that they exist, are dependent on gene-gene interactions in West African populations as detected with ViSEN. In addition, epistatic effects are likely to be influenced by inter- and intra-population differences in genetic or environmental context and/or the mycobacterial lineages causing disease.Genes and Immunity advance online publication, 5 June 2014; doi:10.1038/gene.2014.28.
    Genes and Immunity 06/2014; 15(6). DOI:10.1038/gene.2014.28 · 2.91 Impact Factor
    • "Having known the functional significance of this genetic variant and extensive role of VDR gene and its immune response against TB provided indication of vitamin D-related gene-environment interactions in the host response to TB.[9] Mutations in the VDR gene that impair VDR functions are associated with frequent and severe episodes of infection. Several epidemiological studies have been done in recent past in various ethnic populations to investigate the relationship between TaqI polymorphism and TB risk,[101112131415161718192021222324252627282930] but, they yielded inconsistent and conflicting results. Inconsistency in the results of those studies was mainly attributed to ethnicity of the population, sample size, and individual studies that have low power to examine the overall effect. "
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    ABSTRACT: Objectives: Vitamin D has been shown to hamper the growth of Mycobacterium tuberculosis in macrophages. The actions of vitamin D are exerted through a vitamin D receptor (VDR). The genetic variant TaqI of VDR has been implicated in tuberculosis (TB) risk in several case-control studies. However, these studies have shown inconsistent results. Hence, a meta-analysis was conducted to investigate the potential relationship between VDR TaqI polymorphism and risk of developing TB. Materials and Methods: We performed a quantitative synthesis for published studies based upon the relationship between TaqI polymorphism and TB risk from PubMed (Medline) and Embase databases. The meta-analysis was performed and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for all genetic models. Results: A total of 21 studies including 2,960 TB cases and 3,894 controls were included in this study. The pooled analysis demonstrated no evidence of association between VDR TaqI genotypes and risk of TB in any of the genetic models; variant (t vs T: P = 0.618; OR = 1.051, 95% CI = 0.864–1.278), homozygous (tt vs TT: P = 0.120; OR = 1.336, 95% CI = 0.927–1.924), heterozygous (Tt vs TT: P = 0.925; OR = 0.988, 95% CI = 0.774–1.262), dominant model (tt + Tt vs TT: P = 0.805; OR = 1.032, 95% CI = 0.805–1.322), and recessive model (tt vs TT + Tt: P = 0.180; OR = 1.229, 95% CI = 0.909–1.660). No publication bias was detected during the analysis. Conclusions: Overall findings of this meta-analysis suggest that genetic polymorphism TaqI of VDR gene may not contribute to the risk of TB. However, future larger studies with group of populations are warranted to analyze this relationship.
    Toxicology International 05/2014; 21(2):140-7. DOI:10.4103/0971-6580.139791
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