Genomic dissection of a QTL affecting the lipid profile

描述（由申请人提供）：代谢综合征是一种常见的疾病，在西半球具有冠心病和早期死亡的重大风险。其心血管并发症的核心是该综合征与血浆脂质和脂蛋白谱的特定异常相关，包括血浆甘油三酯升高、高密度脂蛋白胆固醇降低和致密脂蛋白颗粒的优势。为了寻找这种脂质疾病的遗传病因，我们在人类染色体7q36上发现了一个与血浆脂质水平变化密切相关的数量性状位点（QTL）。我们假设这个QTL包含了导致脂质紊乱发生的生物学途径改变的遗传变异。为了验证这一假设，我们提出了一种综合的方法，利用现有的资源和专业知识来识别该QTL中的功能序列变异。具体来说，我们将1.)识别整个QTL区域的单核苷酸多态性（SNPs）及其单倍型和连锁不平衡结构；2)。分析信息性snp与血浆甘油三酯水平、低密度脂蛋白水平和脂蛋白密度分数的关联，使用方差成分连锁/不平衡分析；和3)。使用贝叶斯数量性状核苷酸分析鉴定相关基因或基因组区域的潜在功能序列变异。新基因组技术、新统计方法、DNA和表型信息的综合应用，以及该项目背后聚集的专家联盟，将确保成功阐明这种脂质疾病的遗传病因，从而开发出预防和/或治疗代谢综合征心血管并发症的有效方法。

DESCRIPTION (provided by applicant): The metabolic syndrome is a common disorder posing a significant major risk for coronary heart disease and early mortality in the Western hemisphere. Central to its cardiovascular complications is the association of the syndrome with the specific abnormalities in plasma lipid and lipoprotein profiles including increased plasma triglycerides, decreased HDL cholesterol, and predominance of dense lipoprotein particles. In search for the genetic etiology of this lipid disorder, we identified a quantitative trait locus (QTL) on human chromosome 7q36 strongly linked to variation in plasma lipid levels. We hypothesize that this QTL contains genetic variants that contribute to alterations in biologic pathways underlying the genesis of the lipid disorder. To test for this hypothesis, we propose a comprehensive approach utilizing established resources and expertise to identify the functional sequence variants within this QTL. Specifically, we will 1.) identify single nucleotide polymorphisms (SNPs) and their haplotype and linkage disequilibrium structure across the entire QTL region; 2.) Analyze association of informative SNPs with plasma triglyceride levels, LDL levels, and lipoprotein density fractions using variance component linkage/disequilibrium analyses; and 3.) Identify potentially functional sequence variants in associated genes or genomic regions using Bayesian quantitative trait nucleotide analysis. This comprehensive application of newly available genomic technologies, novel statistical approaches, the DNA and phenotypic information available, and the consortium of expertise assembled behind this project will ensure the successful elucidation of the genetic etiology of this lipid disorder and consequently the development of effective means for prevention and/or treatment of cardiovascular complications of the metabolic syndrome.