Genetics of Infection and its Relationship with CVD Risk

描述（由申请方提供）：心血管疾病（CVD）是大多数人群的主要公共卫生问题。虽然许多研究工作已经针对确定影响个体CVD风险的遗传和环境因素，但感染因子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CVD相关发病率和死亡率的风险。我们建议通过大规模的家族研究，系统地评估人类宿主的遗传因素在调节感染易感性中的作用。在初步工作中，我们已经表明，几种常见的细菌和病毒病原体感染的血清学表型指示是可遗传的。此外，我们已经绘制了一个基因座参与调节易感性肺炎衣原体感染的全基因组连锁分析在墨西哥裔美国家庭。在这个项目中，我们将扩大我们的研究，包括7种常见的病原体-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-在一个更大的谱系样本的2,500墨西哥裔美国人从圣安东尼奥，得克萨斯州。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中的重要性; 3）定位人类基因组中参与感染易感性调节的主要基因; 4）鉴定负责2个重要连锁信号的基因和最可能的功能变体。这个项目利用了3个成熟的家庭研究-圣安东尼奥家庭心脏研究，圣安东尼奥家庭糖尿病/胆囊研究，和退伍军人管理局遗传流行病学研究。全基因组标记基因型已经存在于所有3项研究中。此外，已经测量了多种CVD相关表型，包括炎症标志物。这些研究的血清和血浆样本可用于拟定研究。 与公共卫生的相关性：考虑到这些病原体感染的潜在严重并发症及其对CVD的可能贡献，拟议的研究与公共卫生高度相关，CVD是美国发病率和死亡率的主要贡献者。对感染的遗传方面及其与CVD风险的关系的进一步理解可能会导致预防和治疗感染和CVD的新策略。

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.