CLEC4E (Mincle) genetic variation associates with pulmonary tuberculosis in Guinea-Bissau (West Africa)

被引:8
|
作者
Olvany, Jasmine M. [1 ]
Sausville, Lindsay N. [2 ]
White, Marquitta J. [3 ]
Tacconelli, Alessandra [4 ]
Tavera, Gloria [5 ]
Sobota, Rafal S. [6 ]
Ciccacci, Cinzia [7 ,8 ]
Bohlbro, Anders S. [9 ]
Wejse, Christian [10 ,11 ,12 ,13 ]
Williams, Scott M. [14 ,15 ]
Sirugo, Giorgio [16 ,17 ]
机构
[1] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Cleveland, OH 44106 USA
[3] Univ Calif San Francisco, Dept Med, San Francisco, CA 94158 USA
[4] Osped San Pietro Fatebenefratelli, Ctr Ric, Rome, Italy
[5] Case Western Reserve Univ, Dept Clin Translat Sci Collaborat, Cleveland, OH 44106 USA
[6] Northwestern Univ, Northwestern Mem Hosp, Chicago, IL 60611 USA
[7] St Camillus Int Univ Hlth Sci, UniCamillus, I-00131 Rome, Italy
[8] Univ Roma Tor Vergata, Genet Sect, Dept Biomed & Prevent, Rome, Italy
[9] Aarhus Univ Hosp, Dept Clin Med, Skejby, Denmark
[10] Danish Epidemiol Sci Ctr, Bandim Hlth Project, Bissau, Guinea Bissau
[11] Statens Serum Inst, Bissau, Guinea Bissau
[12] Aarhus Univ Hosp, Dept Infect Dis, Skejby, Denmark
[13] Aarhus Univ, Sch Publ Hlth, Ctr Global Hlth, Skejby, Denmark
[14] Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Cleveland Inst Computat Biol, Cleveland, OH 44106 USA
[15] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland Inst Computat Biol, Cleveland, OH 44106 USA
[16] Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA
[17] Univ Penn, Perelman Sch Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA
基金
美国国家卫生研究院;
关键词
Mycobacterium tuberculosis; Tuberculosis; CLEC4E; Host genetics; Innate immunity; Mincle; MYCOBACTERIUM-TUBERCULOSIS; CANDIDATE GENE; SUSCEPTIBILITY; IMMUNITY; RECEPTOR; POLYMORPHISMS; RECOGNITION;
D O I
10.1016/j.meegid.2020.104560
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
Tuberculosis (TB) is the leading cause of death from a single infectious agent. According to the WHO, 85% of cases in 2018 were pulmonary tuberculosis (PTB), making it the most prevalent form of the disease. Although the bacillus responsible for disease, Mycobacterium tuberculosis (MTB), is estimated to infect 1.7 billion people worldwide, only a small portion of those infected (5-10%) will transition into active TB. Because such a small fraction of infected people develop active disease, we hypothesized that underlying host genetic variation associates with developing active pulmonary disease. Variation in CLEC4E has been of interest in previous association studies showing either no effect or protection from PTB. For our study we assessed 60 SNPs in 11 immune genes, including CLEC4E, using a case-control study from Guinea-Bissau. The 289 cases and 322 controls differed in age, sex, and ethnicity all of which were included in adjusted models. Initial association analysis with unadjusted logistic regression revealed putative association with seven SNPs (p < 0.05). All SNPs were then assessed in an adjusted model. Of the six SNPs that remained significant, three of them were assigned to the CLEC4E gene (rs12302046, rs10841847, and rs11046143). Of these, only rs10841847 passed FDR adjustment for multiple testing. Adjusted regression analyses showed that the minor allele at rs10841847 associated with higher risk of developing PTB (OR = 1.55, CI = 1.22-1.96, p-value = 0.00036). Based on these initial association tests, CLEC4E seemed to be the predictor of interest for PTB risk in this population. Haplotype analysis (2-SNP and 3-SNP windows) showed that minor alleles in segments including rs10841847 were the only ones to pass the threshold of global significance, compared to other haplotypes (p-value< 0.05). Linkage disequilibrium patterns showed that rs12302046 is in high LD with rs10841847 (r(2) = 0.67), and all other SNPs lost significance when adjusted for rs10841847 effects. These findings indicate that rs10841847 in CLEC4E is the single best predictor of pulmonary tuberculosis risk in our study population. These results provide evidence for the hypothesis that genetic variation of CLEC4E influences risk to TB in Guinea-Bissau.
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页数:7
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