Genetic Architecture of Heart Disease in Rural Brazil

描述(由申请人提供)：该项目的最终目标是 查加斯病人群中遗传结构的阐明 居住在巴西农村。在拉丁语中，心脏病的主要原因 在美国，它影响到1600万到1800万人。仅在巴西， 大约10%的人口对克氏锥虫的血清呈阳性， 疾病的寄生原因，亚群经历 血清阳性率高达65%。考虑到大量的主池 这种人畜共患疾病的宿主，彻底根除恰加斯病 通过节肢动物媒介的控制是不可能的。对人类的研究和 动物模型表明，对感染的易感性存在差异， 这种变异可能是由于遗传因素造成的。 因此，这种形式的心脏病代表了一种复杂的表型，具有潜在的 感染易感性和差异的遗传决定因素 疾病发病机制。拟议的项目将检验两个一般假设：1) 宿主遗传因素影响感染的易感性 克氏锥虫，克氏锥虫感染的心脏后果，以及 Chagas病的免疫学相关性，以及2)单个基因座具有 对这些恰加斯病相关特征的可检测的影响。在…的过程中 检验这些假设，我们将1)评估每个个体的基因 大约382个多态短串联重复序列(STR)分布在 基因组，以生成群体特有的10 cM图谱；2)量化 遗传和共同环境因素对克氏毛滴虫感染、心电图的影响 查加斯病的变量和免疫学相关性 3)利用连锁分析 定位影响克氏毛滴虫感染易感性的特定基因， 通过执行全基因组扫描，心电图变量和免疫学相关性 对于使用适当的多点方差分量方法的链接 对于世系延续的人来说。这项研究将是第一次对 对恰加斯病的易感性。

DESCRIPTION (provided by applicant): This project has the ultimate goal of elucidating the genetic architecture of Chagas' disease in a population residing in rural Brazil. A leading cause of heart disease throughout Latin America, it affects between 16 and 18 million individuals. In Brazil alone, approximately 10 percent of the population is seropositive for T. cruzi, the parasitic cause of the disease, with sub-populations experiencing seropositivity rates as high as 65 percent. Given the large pool of primary hosts for this zoonotic disease, complete eradication of Chagas' disease through control of the arthropod vector is unlikely. Research with humans and animal models indicates that there is variation in susceptibility to infection, and disease outcome, and that this variation may be due to genetic factors. Thus, this form of heart disease represents a complex phenotype with potential genetic determinants to both susceptibility to infection and differential disease pathogenesis. The proposed project will test two general hypotheses: 1) that host genetic factors influence susceptibility to infection with Trypanosoma cruzi, cardiac consequences of T. cruzi infection, and immunological correlates of Chagas' disease, and 2) that individual loci have detectable effects on these Chagas' disease related traits. In the process of testing these hypotheses, we will 1) evaluate each individual's genotype for approximately 382 polymorphic short tandem repeats (STRs) spread throughout the genome in order to generate a population specific 10cM map; 2) quantify the effects of genetic and shared environmental factors on T. cruzi infection, ECG variables, and immunological correlates of Chagas' disease in the well-characterized population of Posse; and 3) utilize linkage analysis to localize the specific genes influencing susceptibility to T. cruzi infection, ECG variables, and immunological correlates by performing a genome wide scan for linkage using a multipoint variance component method that is appropriate for extended pedigrees. This study will be the first genome scan for susceptibility to Chagas' disease.