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


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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    ABSTRACT: Although innate immunity came into the research spotlight in the late 1990s when its instructive role in the adaptive immune response was recognized, innate humoral defense factors have a much older history. The exocrine secretions of the body contain a plethora of distinct soluble factors (lysozyme, lactoferrin, peroxidases, proline-rich proteins, histatins, etc.) that protect the body from mucosal microbial pathogens. More recent studies have established that the humoral arm of innate immunity contains a heterogeneous group of pattern-recognition molecules (e.g., pentraxins, collectins, and ficolins), which perform diverse host-defense functions, such as agglutination and neutralization, opsonization, control of inflammation, and complement activation and regulation. These pattern-recognition molecules, which act as functional predecessors of antibodies ("ante-antibodies"), and the classic soluble innate defense factors form an integrated system with complementary specificity, action, and tissue distribution, and they are the subject of this chapter.
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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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    ABSTRACT: Objective The aim of the study was to investigate the association of serum Pentraxin 3 and genotyping with the risk of developing AMI and its severity. Patients and methods Fifty patients admitted to the coronary care unit presented with STEMI (acute ST segment myocardial infarction) at the Cardiology Department, Menoufia University Hospital in the period from October 2014 to April 2015 and another 20 subjects age- and gender-matched were taken as the control group. All patients and control groups were subjected to the following: Full history taking, complete clinical examination. ECG and echocardiography and Laboratory investigation including: estimation of lipid profile, urea and creatinine, CKMB, troponin I, serum pentraxin 3 and Genotyping of pentraxin 3 A/G SNP (rs2305619). Results The patients with myocardial infarction had significantly higher levels of pentraxin 3 than the controls. The cut-off values for PTX3 and troponin I were 4.35 ng/ml and 0.34 μg/l respectively. Pentraxin 3 showed the highest diagnostic accuracy of coronary artery disease (96%), with sensitivity (96%) and specificity (95%). The highest serum pentraxin 3 levels were in the AA mutant homozygous type. Conclusion PTX3 is one of the earliest biomarkers for detecting acute coronary syndrome. rs2305619 AA genotyping of the pentraxin 3 gene might be a candidate risk factor for development of coronary artery disease, presumably by increased pentraxin 3 levels.
    Full-text · Article · Nov 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.
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