Mapping Genes for Atherosclerosis and Insulin Resistance

描述(申请人提供)：心血管疾病(CVD)是西方世界发病率和死亡率的最大原因。心血管疾病的新危险因素包括胰岛素抵抗(IR)和慢性炎症。这一建议及其相关进展R01的假设是，遗传因素在很大程度上负责CVD、IR和炎症之间的相互关系，并且这些因素可以通过在墨西哥裔美国高危人群中使用亚临床病理生理过程的高清晰度表型来识别，例如IR的正常血糖钳和CVD的超声颈动脉内膜-中层厚度(CIMT)。在我们之前的工作中，我们研究了一个庞大的墨西哥裔美国人队列，通过一个冠心病(CAD)的指标病例来确定。该样本前半部分的基因组扫描(SET 1)确定了CIMT、空腹胰岛素和IR的染色体基因座的证据。目标1将通过分析样本的后半部分(集合2)的全基因组扫描来确认这些基因座；然后进行精细作图，目标是优先选择最好的峰，在2到3个峰之间，用于目标2。目标2将测试来自目标1的“最佳”连锁峰下的所有基因，利用越来越多的资源来识别标记的SNP。这种方法同时避免了试图先验决定哪些基因是真正的位置候选基因的局限性，但通过关注基因，比染色体标记方法更有效。每个峰下的所有基因都将在SET 1中进行测试。SET 2将确认阳性结果，目标4中将仅对仍为阳性的基因进行进一步评估。这一两阶段设计提供了识别相关基因的能力，同时将假阳性降至最低。在目标3中，集合1中与IR、空腹胰岛素或CIMT相关的20个生物候选基因将在集合2中进行测试，以确认关联并确定在目标4中研究的基因的优先顺序。在集合2中，将对集合1中与IR、空腹胰岛素或CIMT相关的20个生物候选基因进行测试(n=13)或由连锁进展R01(n=7)建议(并在集合1中测试)。这些基因的单倍型将在集合2中详细描述以供测试。在目标4中，将对集合1中与CIMT、空腹胰岛素和/或IR相关的基因(来自目标2和3)进行测序，并在集合2中进行确认。通过测序发现的新变异将在整个研究人群中进行基因分型，以评估每个基因中似乎对遗传效应负责的最小变异(S)。还将评估基因与基因之间的相互作用。这一建议的一个关键优点是，样本的大小允许在相同的群体中复制(集合1和集合2)连锁和关联结果，具有相同的种族、相同的确定和相同的表型。在这个研究不足的人群中识别CIMT和IR基因将为风险评估和预防提供新的工具。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the largest cause of morbidity and mortality in the Western world. New risk factors for CVD include insulin resistance (IR) and chronic inflammation. The hypothesis of this proposal and its linked Progression R01 is that genetic factors are in significant measure responsible for the interrelationship between CVD, IR and inflammation, and that these can be identified by family studies utilizing high definition phenotyping of subclinical pathophysiologic processes, such as euglycemic clamp for IR and carotid intima-medial thickness (CIMT) by ultrasound for CVD, in a Mexican-American population at high risk for these disorders. In our prior work, we studied a large Mexican-American cohort, ascertained through an index case with coronary artery disease (CAD). Genome scans in the first half of this sample (Set 1) identified evidence for chromosomal loci for CIMT, for fasting insulin, and for IR. Aim 1 will confirm these loci by analysis of a genome wide scan in the second half of the sample (Set 2); followed by fine mapping with the goal of prioritizing the best peaks, between two and three, for use in Aim 2. Aim 2 will test all the genes under the "best" linkage peaks from Aim 1, taking advantage of growing resources that allow identification of tagged SNPs. This approach simultaneously avoids the limitation of trying to a priori decide what genes are true positional candidates, and yet by focusing on genes, is more efficient than a chromosomal marker approach. All genes under each peak will be tested in Set 1. Positive results will be confirmed using Set 2 and only those genes still positive will be evaluated further in Aim 4. This two-stage design provides the power to identify the relevant genes while minimizing false positives. In Aim 3, 20 biologic candidate genes identified as associated with IR, fasting insulin, or CIMT in Set 1, either during the first cycle of the Program (n=13) or suggested by the linked Progression R01 (n=7) (and tested in Set 1), will be tested in Set 2 to confirm the associations and prioritize the genes for study in Aim 4. These genes will have their haplotypes characterized in detail for testing in Set 2. In Aim 4, genes (from Aims 2 and 3) associated with CIMT, fasting insulin, and/or IR in Set 1 and confirmed in Set 2, will be sequenced in individuals with divergent haplotypes and phenotypes. New variants discovered by sequencing will be genotyped in the entire study population to assess the minimum variant(s) within each gene that appear responsible for the genetic effect. Gene-gene interactions will also be evaluated. A key strength of this proposal is that the size of the sample allows replication (Set 1 and Set 2) of both linkage and association results in the same population, with the same ethnicity, same ascertainment, and the same phenotyping. Identifying the genes for CIMT and IR in this understudied population will provide new tools for risk assessment and prevention.