Genetics of Atherosclerosis in Mexican Americans

墨西哥裔美国人动脉粥样硬化的遗传学

• 批准号: 8063980
• 负责人: John Blangero
• 金额: $ 249.11万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063980
• 关键词: Genetics; Atherosclerosis; Mexican; Americans

DESCRIPTION (provided by applicant): This Program Project supports the San Antonio Family Heart Study (SAFHS), the first comprehensive genetic epidemiological study of atherosclerosis and its correlates in Mexican Americans. Its long-term goal is to detect, characterize, map, and identify new polymorphic genes that influence variation in susceptibility to cardiovascular disease (CVD). More than 1,400 members of 41 extended Mexican American families were recruited without regard to disease status and examined during the first grant period (SAFHS1), 859 family members were recalled during the second grant period (SAFHS2), and 950 are being re-examined during the current grant period (SAFHS3). Data from these three examinations includes many quantitative risk factors for CVD, including measures of lipids and lipoproteins, adiposity, insulin and glucose levels, oxidative stress, blood pressure and subclinical measures of atherosclerosis. Genotyping of all family members for >400 markers in a 10 centimorgan map is complete, and many quantitative trait loci (QTLs) for CVD risk factors have been detected and mapped. In the proposed grant period, we begin a new phase that moves beyond QTL localization and is dedicated to the identification and characterization of the genes underlying CVD risk. We propose to follow several of the most promising CVD-risk related QTLs to identify the contributory causal genes. Advanced strategies involving high-density SNP typing, bioinformatic and transcriptional objective prioritization, resequencing, and sophisticated statistical genetic analyses will be employed in Projects 1-3 to achieve these goals. Project 1 will use genetic epidemiologic approaches to follow up findings from the current grant period, including analysis of age-related changes in risk factors and G x E effects; and will analyze newly-available data, including transcriptional profile data, for SAFHS families. Project 2 will pursue gene identification for QTLs related to lipoproteins, oxidative stress, and inflammation. These include QTLs influencing HDL cholesterol levels, oxidized LDL cholesterol levels, and vascular cellular.adhesion molecule 1 levels. Projects will focus on the identification of obesity related QTLs, specifically QTLx influencing total body fat, resistin levels, and waist circumference. A new project, Project 4, will exploit newly generated genome-wide transcriptional profiles for the rapid identification of novel cis-regulated candidate genes. This project will explore regulatory variation in the proximal promoter elements of 50 cis-regulated genes whose expression is correlated with triglyceride or HDL cholesterol levels.

描述（由申请人提供）：本项目支持圣安东尼奥家庭心脏研究（SAFHS），这是墨西哥裔美国人动脉粥样硬化及其相关性的第一项综合遗传流行病学研究。其长期目标是检测，表征，映射和识别影响心血管疾病（CVD）易感性变化的新多态性基因。在第一个补助期（SAFHS 1）内，招募了41个墨西哥裔美国人大家庭的1,400多名成员，不考虑疾病状况，并进行了检查，在第二个补助期（SAFHS 2）内召回了859名家庭成员，在当前补助期（SAFHS 3）内重新检查了950名家庭成员。这三项检查的数据包括许多CVD的定量风险因素，包括脂质和脂蛋白、肥胖、胰岛素和葡萄糖水平、氧化应激、血压和动脉粥样硬化的亚临床指标。在10 centimorgan图谱中对所有家族成员的> 400个标记的基因分型已经完成，并且已经检测和定位了CVD危险因素的许多数量性状基因座（QTL）。在拟议的授权期间，我们开始一个新的阶段，超越QTL定位，并致力于识别和表征的基因基础CVD风险。我们建议遵循几个最有希望的CVD风险相关的QTL，以确定贡献的致病基因。涉及高密度SNP分型，生物信息学和转录目标优先级，重测序和复杂的统计遗传分析的先进策略将在项目1 - 3中采用，以实现这些目标。项目1将使用遗传流行病学方法来跟踪当前资助期的发现，包括分析与年龄相关的风险因素变化和G x E效应;并将分析SAFHS家庭的新数据，包括转录谱数据。项目2将对与脂蛋白、氧化应激和炎症相关的QTL进行基因鉴定。这些包括影响HDL胆固醇水平、氧化LDL胆固醇水平和血管细胞粘附分子1水平的QTL。项目将集中于确定肥胖相关的QTL，特别是影响全身脂肪，体重水平和腰围的QTLx。一个新的项目，项目4，将利用新产生的全基因组转录谱快速识别新的顺式调节的候选基因。本研究将探讨50个顺式调控基因的近端启动子元件的调控变异，这些基因的表达与甘油三酯或高密度脂蛋白胆固醇水平相关。