Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways.
Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways.
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DOI：
10.1186/1471-2334-13-587
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发表时间：
2013-12-12
影响因子：
3.7
通讯作者：
Chevillard C
中科院分区：
文献类型：
--
作者：
Frade AF;Pissetti CW;Ianni BM;Saba B;Lin-Wang HT;Nogueira LG;de Melo Borges A;Buck P;Dias F;Baron M;Ferreira LR;Schmidt A;Marin-Neto JA;Hirata M;Sampaio M;Fragata A;Pereira AC;Donadi E;Kalil J;Rodrigues V;Cunha-Neto E;Chevillard C
由原生动物克氏锥虫引起的恰加斯病是拉丁美洲的地方病。30%的感染者会发展成慢性恰加斯心肌病（CCC），这是一种炎症性扩张型心肌病，是迄今为止锥虫病最重要的临床后果。克氏感染其他人保持无症状（ASY）。一个可能的遗传因素，以疾病进展的情况下，家族聚集性和先天性和适应性免疫基因的标记与CCC发展的关联。Th 1型T细胞的迁移在心肌损伤中起主要作用。我们的遗传分析集中在CCR 5，CCL 2和MAL/TIRAP基因。我们使用基于标签SNP的方法，定义为捕获每个基因的所有遗传信息。这项研究是在一个庞大的巴西人群中进行的，包括315例CCC病例和118例ASY受试者。CCL 2 rs 2530797 A/A和TIRAPrs 8177376 A/A与CCC易感性增加相关，而CCR 5 rs3176763 C/C基因型与CCC保护相关。当我们将分析限制在以左心室射血分数低于40%为特征的重度CCC时，这些相关性得到了证实。我们的数据表明，多态性影响参与几个免疫参数（先天免疫信号转导和T细胞/单核细胞迁移）的关键分子在遗传易感性CCC发展中发挥作用。这也指出了CCC的多基因特征，每个多态性赋予一个小的贡献。CCC遗传标记的鉴定将为CCC的发病机制和治疗靶点提供信息。
Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage. Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects. The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%. Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.