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。人类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、不完全遗传和环境影响而复杂化。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学的能力的提高，评估动脉粥样硬化过程的临床前生理和结构方面的能力，高度多态性分子遗传标记的发现，复杂性状分析的新策略的开发，而相关的统计程序也使得即使是对疾病有微小贡献的基因的识别变得触手可及。因此，基因鉴定中的限速步骤是研究足够生理细节和足够样本量的家族，以匹配遗传标记和分析技术的能力。项目2的目标是利用我们在详细的广泛的家族表型分析中的经验，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，特别强调血管壁的结构变化，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组成部分。由于动脉粥样硬化过程的各个组成部分有许多潜在的候选基因，因此系统的作图方法是特别合适的。因此，我们提出了一个两阶段的设计，包括一个初始的全基因组扫描与10cM的地图，随后在选定的区域进行精细映射，然后确认在一个独立的样本中的连锁，使用高度多态性的分子标记在2套约112个广泛的表型墨西哥裔美国家庭，共有超过1800 sibpairs。精细定位的区域将根据连锁分析的显著性水平、已知候选基因或小鼠同线区域的存在来选择。将通过候选基因关联和分层分析进一步检查确认的连锁。

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.