Candidate genes-based investigation of susceptibility to Human African Trypanosomiasis in Côte d'Ivoire.
Candidate genes-based investigation of susceptibility to Human African Trypanosomiasis in Côte d'Ivoire.
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DOI：
10.1371/journal.pntd.0005992
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发表时间：
2017-10
影响因子：
3.8
通讯作者：
TrypanoGEN Research Group as members of The H3Africa Consortium
中科院分区：
文献类型：
--
作者：
Ahouty B;Koffi M;Ilboudo H;Simo G;Matovu E;Mulindwa J;Hertz-Fowler C;Bucheton B;Sidibé I;Jamonneau V;MacLeod A;Noyes H;N'Guetta SP;TrypanoGEN Research Group as members of The H3Africa Consortium
非洲人类锥虫病（HAT）或昏睡病是一种被忽视的热带疾病。长期以来，冈比亚锥虫被视为一种必然致命的疾病，越来越多的证据表明，冈比亚锥虫感染可导致多种临床结果，包括潜伏性感染，即通过显微镜无法检测到寄生虫的长期感染。这种临床多样性的决定因素尚不清楚，但可能部分归因于寄生虫或宿主多种基因的遗传多样性，或它们之间的相互作用。在Côte科特迪瓦进行了一项候选基因关联研究，采用病例对照设计，共纳入233名受试者（100例活动性HAT病例，100例对照和33例潜伏性感染）。使用16个候选基因（IL1、IL4、IL4R、IL6、IL8、IL10、IL12、IL12R、TNFA、INFG、MIF、APOL1、HPR、CFH、HLA-A和HLA-G）的96个snp对三种表型之间的所有三种可能的两两比较进行检验。77个snp的数据通过了质量控制。在活动性病例和对照组的比较中，il - 6和TNFA中有3个位点存在相关性；潜伏性感染病例和活动性病例的比较中，APOL1、MIF和IL6各有1个SNP；潜伏性感染病例和对照组的比较中，IL4、HLA-G和TNFA中有7个SNP。在Bonferroni校正后，没有显著的关联，但Benjamini Hochberg错误发现率检验表明，至少有一些关联是真实的。尽管可用的样本数量很少，但与潜伏感染的过量关联表明，这些受试者形成了不同于活性HAT病例和对照组的独特遗传聚类，尽管主成分分析未观察到表型聚类。这强调了宿主遗传多态性和寄生虫多样性之间相互作用的复杂性。自首次发现以来，非洲人类锥虫病（HAT）或昏睡病一直被描述为总是致命的。然而，最近的数据表明，冈比亚锥虫感染可在其人类宿主中导致广泛的临床结果，包括可通过抗体检测到的长期感染，但在显微镜下无法看到寄生虫；这些病例被称为潜伏感染。虽然决定这种不同反应的因素尚未明确表征，但免疫反应的效应者已被部分牵连为关键参与者。我们从Côte科特迪瓦流行疫源地的活动性HAT、潜伏性感染和控制人群中收集了样本。通过候选基因关联研究，我们检测了16个基因的单核苷酸多态性（SNPs）在HAT易感性/抗性中的作用。有证据表明，IL4、IL6、APOL1、HLAG、MIF和TNFA基因的变异可改变HAT的发生风险。这些蛋白质调节对许多感染的炎症反应或直接参与杀死寄生虫。在这项研究中，结果在统计上是薄弱的，并且本身是不确定的，然而其他研究也发现了这些基因的关联，增加了我们已经确定的变异在Côte科特迪瓦对锥虫感染的反应中发挥真正作用的机会。
Human African Trypanosomiasis (HAT) or sleeping sickness is a Neglected Tropical Disease. Long regarded as an invariably fatal disease, there is increasing evidence that infection by T. b. gambiense can result in a wide range of clinical outcomes, including latent infections, which are long lasting infections with no parasites detectable by microscopy. The determinants of this clinical diversity are not well understood but could be due in part to parasite or host genetic diversity in multiple genes, or their interactions. A candidate gene association study was conducted in Côte d’Ivoire using a case-control design which included a total of 233 subjects (100 active HAT cases, 100 controls and 33 latent infections). All three possible pairwise comparisons between the three phenotypes were tested using 96 SNPs in16 candidate genes (IL1, IL4, IL4R, IL6, IL8, IL10, IL12, IL12R, TNFA, INFG, MIF, APOL1, HPR, CFH, HLA-A and HLA-G). Data from 77 SNPs passed quality control. There were suggestive associations at three loci in IL6 and TNFA in the comparison between active cases and controls, one SNP in each of APOL1, MIF and IL6 in the comparison between latent infections and active cases and seven SNP in IL4, HLA-G and TNFA between latent infections and controls. No associations remained significant after Bonferroni correction, but the Benjamini Hochberg false discovery rate test indicated that there were strong probabilities that at least some of the associations were genuine. The excess of associations with latent infections despite the small number of samples available suggests that these subjects form a distinct genetic cluster different from active HAT cases and controls, although no clustering by phenotype was observed by principle component analysis. This underlines the complexity of the interactions existing between host genetic polymorphisms and parasite diversity. Since it was first identified, human African trypanosomiasis (HAT) or sleeping sickness has been described as invariably fatal. Recent data however suggest that infection by T. b. gambiense can result in a wide range of clinical outcomes in its human host including long lasting infections, that can be detected by the presence of antibodies, but in which parasites cannot be seen by microscopy; these cases are known as latent infections. While the factors determining, this varied response have not been clearly characterized, the effectors of the immune responses have been partially implicated as key players. We collected samples from people with active HAT, latent infections and controls in endemic foci in the Côte d’Ivoire. We tested the role of single nucleotide polymorphisms (SNPs) in 16 genes on susceptibility/resistance to HAT by means of a candidate gene association study. There was some evidence that variants of the genes for IL4, IL6, APOL1, HLAG, MIF and TNFA modified the risk of developing HAT. These proteins regulate the inflammatory response to many infections or are directly involved in killing the parasites. In this study, the results were statistically weak and would be inconclusive on their own, however other studies have also found associations in these genes, increasing the chance that the variants that we have identified play a genuine role in the response to trypanosome infection in Côte D’Ivoire.
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DOI：
10.1126/science.1193032
发表时间：
2010-08-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Genovese G;Friedman DJ;Ross MD;Lecordier L;Uzureau P;Freedman BI;Bowden DW;Langefeld CD;Oleksyk TK;Uscinski Knob AL;Bernhardy AJ;Hicks PJ;Nelson GW;Vanhollebeke B;Winkler CA;Kopp JB;Pays E;Pollak MR
通讯作者：
Pollak MR
影响因子：
3.8
作者：
Jamonneau V;Ilboudo H;Kaboré J;Kaba D;Koffi M;Solano P;Garcia A;Courtin D;Laveissière C;Lingue K;Büscher P;Bucheton B
通讯作者：
Bucheton B
影响因子：
30.8
作者：
Knight, JC;Udalova, I;Kwiatkowski, D
通讯作者：
Kwiatkowski, D
影响因子：
6.4
作者：
Daulouède, S;Bouteille, B;Vincendeau, P
通讯作者：
Vincendeau, P
影响因子：
3.2
作者：
Courtin, David;Milet, Jacqueline;Garcia, Andre
通讯作者：
Garcia, Andre