Genetics of Infection and its Relationship with CVD Risk

描述(由申请人提供)：心血管疾病(CVD)是大多数人类群体的主要公共卫生问题。虽然许多研究都致力于确定影响个人心血管疾病风险的遗传和环境因素，但感染性病原体在疾病病因学中的潜在参与相对较少受到关注，尽管有大量证据表明，感染有助于炎症并增加与心血管疾病相关的发病率和死亡率。我们建议通过一项大规模的家庭研究，系统地评估人类宿主的遗传因素在调节感染易感性方面的作用。在初步工作中，我们已经证明，感染几种常见细菌和病毒病原体的血清学表型是可遗传的。此外，我们还通过全基因组连锁分析，在墨西哥裔美国家庭中定位了一个参与调节肺炎衣原体感染易感性的基因座。在这个项目中，我们将扩大我们的研究范围，以涵盖7种常见病原体-肺炎衣原体、幽门螺杆菌、牙龈卟啉单胞菌、巨细胞病毒、甲型肝炎病毒、单纯疱疹病毒1和人类疱疹病毒8-来自德克萨斯州圣安东尼奥的2,500名墨西哥裔美国人的家系样本。该项目的4个主要目标是：1)确定感染和炎症的表型和遗传相关性；2)评估宿主基因在调节感染易感性方面的重要性；3)在人类基因组中定位参与调节感染易感性的主要基因；以及4)确定负责2个显著连锁信号的基因(S)和最有可能的功能变异(S)。该项目利用了3项久负盛名的家庭研究-圣安东尼奥家庭心脏研究、圣安东尼奥家庭糖尿病/胆囊病研究和退伍军人管理局遗传流行病学研究。在所有3项研究中都已经存在全基因组标记的基因类型。此外，已经测量了包括炎症标记物在内的各种与心血管疾病相关的表型。这些研究的血清和血浆样本可用于拟议的研究。 与公共卫生的相关性：鉴于这些病原体感染的潜在严重并发症及其对心血管疾病的可能贡献，拟议的研究与公共卫生高度相关，心血管疾病是美国发病率和死亡率的主要贡献者。更好地了解感染的遗传方面及其与心血管疾病风险的关系可能导致预防和治疗感染和心血管疾病的新战略。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is a major public health concern in most human populations. While much research effort has been directed towards identifying the genetic and environmental factors that influence an individual's risk of CVD, the potential involvement of infectious agents in disease etiology has received comparatively little attention, despite substantial evidence that infections contribute to inflammation and elevate the risk of CVD-related morbidity and mortality. We propose to assess the role of genetic factors of the human host in regulating susceptibility to infection in a systematic manner by means of a large-scale family study. In preliminary work, we have shown that serological phenotypes indicative of infection with several common bacterial and viral pathogens are heritable. Furthermore, we have mapped a locus involved in regulating susceptibility to infection by Chlamydia pneumonias by genome-wide linkage analysis in Mexican American families. In this project, we will expand our research to encompass 7 common pathogens---Chlamydia pneumoniae, Helicobacter pylori, Porphyromonas gingivalis, cytomegalovirus, hepatitis A virus, herpes simplex virus 1, and human herpesvirus 8---in a much larger pedigree sample of 2,500 Mexican Americans from San Antonio, TX. The 4 main goals of the project are to: 1) determine the phenotypic and genetic correlation of infection and inflammation; 2) assess the importance of host genes in regulating susceptibility to infection; 3) localize major genes involved in regulation of infection susceptibility in the human genome; and 4) identify the gene(s) and most likely functional variant(s) responsible for 2 significant linkage signals. This project takes advantage of 3 well-established family studies---the San Antonio Family Heart Study, the San Antonio Family Diabetes/Gallbladder Study, and the Veterans Administration Genetic Epidemiology Study. Genome-wide marker genotypes already exist in all 3 studies. In addition, a variety of CVD-related phenotypes, including inflammation markers, have already been measured. Serum and plasma samples from these studies are available for use in the proposed research. Relevance to Public Health: The proposed research is highly relevant to public health, given the potentially serious complications of infections with these pathogens and their likely contribution to CVD, which is a major contributor to morbidity and mortality in the US. Improved understanding of the genetic aspects of infection and its relationship with CVD risk may lead to novel strategies for prevention and treatment of infection and CVD.