MAPPING THE GENES FOR ATHEROSCLEROSIS AND INSULIN RESISTANCE

动脉粥样硬化是西方世界发病率和死亡率的主要原因。受试者动脉粥样硬化的研究因非孟德尔遗传、遗传异质性、发病年龄晚、外显性不全和环境影响而变得复杂。然而，最近的进展，包括我们描述与胰岛素抵抗和相关代谢综合征相关的异常生理的能力的提高，评估动脉粥样硬化过程的临床前生理和结构方面的能力，高度多态的分子遗传标记的发现，复杂性状分析的新策略的发展，以及相关的统计程序，使得识别对疾病有轻微贡献的基因变得近在咫尺。因此，基因鉴定的速度限制步骤是对家系进行充分的生理细节和足够的样本大小的研究，以匹配遗传标记和分析技术的力量。项目2的目标是利用我们在详细、广泛的家族表型分析方面的经验，确定人类基因组中导致动脉粥样硬化中间表型的特定基因和区域，特别是通过超声评估颈动脉内膜中层厚度(IMT)、胰岛素抵抗和相关代谢综合征的成分来确定血管壁的结构变化。系统的定位方法特别合适，因为动脉粥样硬化过程的各个组成部分有如此多的潜在候选基因。因此，我们提出了一个两阶段设计，包括用10 cM图谱进行初始全基因组扫描，然后在选定的区域进行精细定位，然后在独立样本中使用高度多态的分子标记，在两组广泛表型的墨西哥裔美国人家庭中使用高度多态的分子标记，每组大约112个，总共超过1800个同胞对。精细定位的区域将根据连锁分析的显著水平、是否存在已知的候选基因或小鼠共线区域来选择。已确认的关联将通过候选基因关联和分层分析进行进一步检验。

Atherosclerosis is the major cause of morbidity and mortality in the western world. Studies of atherosclerosis in human subjects are complicated by non- Mendelian inheritance, genetic heterogeneity, a late age of onset, incomplete penetrance, and environmental influences. However, recent advances, including our improved ability to delineate the abnormal physiology related to insulin resistance and associated metabolic syndrome, the ability to assess preclinical physiological and structural aspects of the atherosclerotic process, the discovery of highly polymorphic molecular genetic markers, the development of new strategies for analysis of complex traits, and the relevant statistic programs have put the identification of genes making even modest contributions to the disease within reach. As a consequence, the rate limiting step in gene identification is the study of families in sufficient physiologic detail and in adequate sample size to match the power of the genetic marker and analytic technology. The goal of Project 2 is to utilize our experience in detailed extensive family phenotyping to identify specific genes and regions within the human genome contributing to intermediate phenotypes for atherosclerosis with particular emphasis on structural changes in the vessel wall, defined by a ultrasound assessment of carotid intimal medial thickness (IMT), and insulin resistance and components of the associated metabolic syndrome. A systematic mapping approach is particular appropriate since there are so many potential candidate genes for the various components of the atherosclerosis process. We therefore propose a two stage design consisting of an initial whole genome scan with a 10cM map, followed by fine mapping in selected regions, then confirming the linkage in an independent sample, using highly polymorphic molecular markers in 2 sets of approximately 112 each of extensively phenotyped Mexican-American families with a total of over 1800 sibpairs. The regions for fine mapping will be selected on the basis of the significance level of the linkage analyses, existence of known candidate genes or mouse syntenic regions. The confirmed linkages will be further examined by candidate gene association and stratified analyses.