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 阐明人群中恰加斯病的遗传结构 居住在巴西农村。拉丁美洲心脏病的主要原因 在美国，它影响了1600万到1800万人。仅在巴西， 大约10%的人口是T.克鲁济 寄生虫引起的疾病，与亚人群经历 血清阳性率高达65%。鉴于主要的 这种人畜共患疾病的宿主，彻底根除恰加斯病 通过控制节肢动物传播媒介是不可能的。人类研究和 动物模型表明对感染的易感性存在差异， 和疾病的结果，这种变化可能是由于遗传因素。 因此，这种形式的心脏病代表了一种复杂的表型， 对感染易感性和不同的遗传决定因素 发病机理拟议的项目将测试两个一般假设：1） 宿主遗传因素影响感染的易感性， 克氏锥虫、T. Cruzi感染，以及 恰加斯病的免疫学相关性，以及2）单个基因座具有 对南美锥虫病相关性状的影响过程中 为了验证这些假设，我们将1）评估每个人的基因型， 大约有382个多态性短串联重复序列（STR）分布在整个 基因组，以产生群体特异性10 cM图谱; 2）定量 遗传因素和共同环境因素对T.克氏感染，心电图 变量和免疫学相关性的查加斯病在 充分表征的波塞群体;和3）利用连锁分析， 定位影响T易感性的特异基因。克氏感染， ECG变量和免疫学相关性，通过进行全基因组扫描 对于使用多点方差分量方法的链接， 为了扩大血统。这项研究将是首次基因组扫描， 对南美锥虫病的易感性。

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.