Genetics of Coronary Artery Disease in Alaska Natives

描述(由申请人提供)： GOCADAN(阿拉斯加土著冠状动脉疾病遗传学)是一项研究阿拉斯加诺顿湾地区爱斯基摩人心血管疾病(CVD)的遗传和环境因素的相对贡献的研究。随着阿拉斯加爱斯基摩人的生活方式和传统饮食西化，心血管疾病及其风险因素正在迅速增加。在第一阶段，我们收集了1214名GOCADAN参与者的家庭数据。对表型数据的初步分析显示，动脉粥样硬化斑块和自我报告的心血管疾病的患病率很高，存在有利的脂蛋白、血压和胰岛素抵抗特征，但吸烟、病原体负担和C反应蛋白(CRP)水平较高。我们的遗传分析表明，关键的心血管疾病危险因素具有显著的遗传力，并检测到心血管疾病相关表型的多效性效应。我们的初步基因组扫描发现了与心血管疾病相关的表型有希望的数量性状基因座(QTL)，包括位于染色体2q上的糖尿病QTL，位于染色体19的血脂水平QTL，以及位于染色体2p上的血压表型QTL。由于到目前为止收集的数据提出了许多关于基因和环境对该人群中动脉粥样硬化斑块和心血管疾病高发的亲属贡献的悬而未决的问题，我们建议继续这项研究，具体目的如下：1)使用贝叶斯数量性状核苷酸(QTN)分析来检查靠近心血管疾病危险因素QTL的位置候选基因，以确定导致我们连锁信号的遗传变异；2)继续对在第一阶段和第二阶段检查中收集的与心血管疾病相关的表型进行全基因组连锁和其他定量遗传分析，包括在第二阶段收集的新表型，3)在第一阶段(基线)和第二阶段(后续)检查之间评估基因对心血管疾病相关表型变化的贡献；4)继续作为数据协调中心，并在第二阶段家庭成员复查中为诺顿健康公司、MedStar研究所和康奈尔医学中心提供资源。这项研究在确定与生活方式和饮食相互作用的遗传因素以增加阿拉斯加爱斯基摩人和普通人群的心血管疾病易感性方面应该被证明是非常有价值的。GOCADAN将为爱斯基摩人和其他人群带来有价值的治疗和预防战略，这些人群的肥胖症、糖尿病和心血管疾病的流行正在迅速增加。

DESCRIPTION (provided by applicant): GOCADAN (Genetics of Coronary Artery Disease in Alaska Natives) is a study of the relative contributions of genetic and environmental factors to cardiovascular disease (CVD) in Eskimos in the Norton Sound region of Alaska. CVD and its risk factors are increasing rapidly in Alaska Eskimos as their lifestyle and traditional diets become westernized. During Phase I, we have collected family data on 1214 GOCADAN participants. Initial analyses of the Phenotypic data show a high prevalence of atherosclerotic plaque and self-reported CVD, in the presence of favorable lipoprotein, blood pressure, and insulin resistance profiles, but high levels of smoking, pathogen burden, and C-reactive protein (CRP). Our genetic analyses show that key CVD risk factors have significant heritabilities, and have detected pleiotropic effects on CVD- related phenotypes. Our initial genome scan has identified promising quantitative trait loci (QTLs) for CVD-related phenotypes including a QTL for diabetes on chromosome 2q, a QTL for lipid levels on chromosome 19, and a QTL for blood pressure phenotypes on chromosome 2p. Because the data collected so far raise many unanswered questions concerning the relatives contribution of genes and environment to the high prevalence of atherosclerotic plaque and CVD in this population, we propose to continue this study with the following specific aims: 1) examine positional candidate genes in proximity to CVD risk factor QTLs using Bayesian quantitative trait nucleotide (QTN) analysis to identify genetic variation that accounts for our linkage signals, 2) continue genome-wide linkage and other quantitative genetic analyses of CVD-related phenotypes collected in Phase I and II examinations, including new phenotypes collected in Phase II, 3) assess the genetic contribution to changes in CVD-related phenotypes between Phase I (baseline) and Phase II (follow-up) examinations, and 4) continue to serve as the Data Coordinating Center and as a resource for Norton Sound Health Corporation, MedStar Research Institute and Cornell Medical Center in the Phase II re-examination of family members. This study should prove invaluable in the identification of genetic factor that interact with lifestyle and diet to increase susceptibility to CVD in both Alaskan Eskimos and the general population. GOCADAN will lead to valuable therapeutic and prevention strategies for Eskimos and other populations, where the epidemics of obesity, diabetes, and CVD are increasing rapidly.