Genomewide Association Study of Lipid Response to Fenofibrate and Dietary Fat

描述(申请人提供)：肥胖、代谢综合征和糖尿病发病率的急剧上升激发了人们对影响甘油三酯升高、低高密度脂蛋白和高非高密度脂蛋白的干预作用的兴趣。虽然低密度脂蛋白-C是NCEP-ATP-3指南的重点，但高密度脂蛋白-C和TGS也是危险的决定因素。遗传变异会影响血脂水平及其对环境因素的反应，尽管这种变异反应的遗传基础还没有得到很好的描述。为了进一步研究脂类和脂蛋白的遗传基础及其对环境的响应，我们提出了降脂和饮食网络(GOLDN)的全基因组关联(GWA)研究，GOLDN是NHLBI基因-环境相互作用(PROGENI)协作计划中的四个网络之一。GOLDN是一项以家庭为基础的干预研究，旨在确定决定脂质(TGS、高密度脂蛋白-C、低密度脂蛋白-C、核磁共振测量的颗粒大小)对两种干预措施的反应的基因组区域，一种是提高血脂(摄入83%脂肪，700千卡/平方米的膳食)，另一种是降低血脂(非诺贝特治疗160 mg，qd，为期3周)。其他表型包括脂联素、葡萄糖和炎症标志物(CRP、TNF1、MCP1、IL-2可溶性受体、IL-6)。征聘和后续行动于2005年秋季完成(n=1123人完成)。高脂餐干预期间，分别于餐后0、3.5、6h采集空腹血脂和脂蛋白，非诺贝特干预分别于0、1、20、21d采集空腹血脂和脂蛋白。具体地说，我们建议：(I)使用Affymetrix 6.0阵列对所有参与者进行基因分型。(Ii)使用控制人群分层的混合模型，利用新颖的结构化关联检验，测试遗传变异与干预表型(在进食后3.5小时和6小时测量的餐后血脂，以及非诺贝特后的脂)之间的相关性。将控制误发现率的方法用于多次测试。对于炎症和药物遗传变量，将评估遗传-脂质关联的混杂。(3)为在外部群体中复制做好准备。我们将通过考虑我们在GOLDN内不断演变的连锁证据和候选基因证据的背景下的发现，以及伴随的NHLBI GWA研究的结果，确定与脂质和脂蛋白基线或干预表型最显著相关的1,500个SNP和多达1500个变异体。尽管目前的提案没有要求为推广提供资金，但我们已经从其他三项研究中获得了合作意向的协议。在复制之后，未来的研究将通过检查与基因干预相互作用相关的变体的功能相关性来扩展拟议的工作。对对高脂饮食反应不佳或对非诺贝特反应良好的个体进行基因分型，可能使有针对性的干预措施能够减少血脂异常，并为临床实践找到有效的治疗方法。公共卫生相关性：卫生官员早就认识到脂肪和胆固醇在肥胖、糖尿病和心脏病等疾病和疾病中的重要作用。然而，人们的基因如何与他们的饮食脂肪摄入量或他们的降血脂药物治疗相互作用却知之甚少。这项拟议的项目旨在识别影响脂肪和胆固醇对饮食和药物反应的基因变异；这些知识有朝一日可能会帮助医生根据个人的遗传天赋定制预防措施和治疗方法。

DESCRIPTION (provided by applicant): The dramatic rise in the incidence of obesity, metabolic syndrome, and diabetes has fueled interest to understand the role of interventions which affect elevated triglycerides (TGs), low HDL-C, and high non- HDL-C. Although LDL-C is a focus of NCEP-ATP-3 guidelines, HDL-C and TGs are also implicated as determinants of risk. Genetic variation influences lipid levels and their response to environmental factors, although the genetic basis of the variable response is not well described. To further characterize the genetic basis of lipids and lipoproteins and their response to environment, we propose a whole-genome association (GWA) study for the Genetics of Lipid Lowering and Diet Network (GOLDN), one of 4 networks in the NHLBI Programs in Gene-Environment Interaction (PROGENI) collaboration. GOLDN is a family-based intervention study designed to identify genomic regions that determine response of lipids (TGs, HDL-C, LDL-C, NMR-measured particle sizes) to 2 interventions, one to raise lipids (ingestion of an 83% fat, 700 kcals/m2 meal) and one to lower lipids (fenofibrate treatment 160 mg qd for 3 weeks). Additional phenotypes include adiponectin, glucose, and inflammatory markers (CRP, TNF1, MCP1, IL-2 soluble receptor, IL-6). Recruitment and follow up were completed in the fall of 2005 (n=1123 completed). During the high-fat meal intervention, fasting lipids and lipoproteins were collected at 0, 3.5 and 6 hours after the meal, and for the fenofibrate intervention, fasting lipid and lipoproteins were collected at days 0, 1, 20 and 21. Specifically, we propose to: (i) Genotype all participants using the Affymetrix 6.0 array. (ii) Test associations between genetic variants and intervention phenotypes (post-prandial lipids measured at 3.5 and 6 hours after ingestion of the meal, and post-fenofibrate lipids) using a mixed model controlling for population stratification using novel structured-association testing. False discovery rate methods will control for multiple testing. Confounding of genetic-lipid associations will be assessed for inflammatory and pharmacogenetic variables. (iii) Prepare for replication in external cohorts. We will identify 1,500 SNPs most significantly associated with lipid and lipoprotein baseline or intervention phenotypes and up to 1500 more variants by considering our findings in the context of evolving linkage evidence and candidate gene evidence within GOLDN, and findings from concomitant NHLBI GWA studies. Although the current proposal does not request funds for replication, we have already secured agreements from three other studies conveying intent to collaborate. Following replication, future research will extend the proposed work by examining the functional relevance of variants associated with gene-by-intervention interactions. Genotypic characterization of individuals who respond poorly to a high-fat diet or favorably to fenofibrate may enable targeted interventions to reduce dyslipidemia and identify effective treatments for clinical practice. PUBLIC HEALTH RELEVANCE: Health officials have long recognized the important role fat and cholesterol play in conditions and diseases such as obesity, diabetes, and heart disease. However, how people's genes interact with their consumption of dietary fat or their treatment with drugs to reduce blood fats is poorly understood. The proposed project aims to identify genetic variants that influence fat and cholesterol's response to diet and drugs; this knowledge may someday help doctors tailor prevention efforts and treatments based on individuals' genetic endowment.