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，在西半球构成冠心病和早期死亡的重大风险。其心血管并发症的中心是该综合征与血浆脂质和脂蛋白谱的特定异常的相关性，包括血浆甘油三酯升高、HDL胆固醇降低和致密脂蛋白颗粒占优势。为了寻找这种脂质紊乱的遗传病因，我们在人类染色体7 q36上发现了一个与血脂水平变化密切相关的数量性状位点（QTL）。我们假设，这个QTL包含遗传变异，有助于改变生物学途径的脂质紊乱的起源。为了验证这一假设，我们提出了一个综合的方法，利用现有的资源和专业知识，以确定该QTL内的功能序列变异。具体来说，我们将1.）鉴定单核苷酸多态性（SNP）及其在整个QTL区域的单倍型和连锁不平衡结构; 2.）使用方差分量连锁/不平衡分析来分析信息性SNP与血浆甘油三酯水平、LDL水平和脂蛋白密度级分的关联;以及3.）使用贝叶斯数量性状核苷酸分析识别相关基因或基因组区域中的潜在功能序列变体。这种新的可用的基因组技术，新的统计方法，DNA和表型信息的综合应用，以及该项目背后的专业知识联盟将确保成功阐明这种脂质紊乱的遗传病因，从而开发有效的手段预防和/或治疗代谢综合征的心血管并发症。

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.