Genetics and Personalized Medicine: From Population Studies to Clinical Therapy

描述(申请人提供)：我们建议扩大心血管疾病预防中心的研究重点，聘请一名受过人类遗传学培训的独立教员，他将在贝勒医学院医学系和分子与人类遗传学系联合受聘，在两个与改善冠心病(CHD)预防直接相关的主要领域进行研究。他/她将建立有效的工具，根据遗传变异，主要是单核苷酸多态(SNPs)来评估和分层冠心病风险。他/她将在一个由甘油三酯或高密度脂蛋白胆固醇上下限个体组成的特殊亚群中，全面描述影响高密度脂蛋白胆固醇(HDL-C)、甘油三酯(TG)和冠心病的已知和新基因和基因组区域。这一方法的总体策略有明确的治疗目标：1.根据个体的遗传信息，更准确地预测和分类风险，从而能够进行更适当的预防性治疗。2.鉴定与高密度脂蛋白胆固醇、甘油三酯、冠心病风险相关的基因和基因组区域，以及对治疗血脂紊乱的常用药物的反应。实现这些目标将发展和扩大已经在进行的机构间和机构内合作。来自美国最大的前瞻性队列研究-社区动脉粥样硬化风险(ARIC)、候选基因协会资源(CARE)和心脏和衰老研究基因组流行病学(CHARE)研究的队列-将由Recruit与贝勒医学院分子和人类遗传学系以及德克萨斯大学公共卫生学院人类遗传学中心密切合作进行分析，以确定与低高密度脂蛋白-C、高甘油三酯和冠心病风险相关的SNPs。联合研究发现的基因将由贝勒医学院的人类基因组测序中心对参与他汀类和贝特类药物治疗的双盲研究的低高甘油三酯患者群体进行测序，以检查基因序列变异与高密度脂蛋白和甘油三酯水平的关联，并确定这些基因对常用药物引起的血脂变化的影响。因此，遗传信息将被应用于努力完善CHD风险评估，并通过个性化的预防性治疗提高风险降低。 心血管疾病仍然是美国死亡和医疗费用的主要原因。通过利用最近的基因发现来确定谁有心脏病发作的风险，并通过更好地了解控制血液中脂肪(甘油三酯和高密度脂蛋白)水平的基因，可以改善心血管疾病的预防。

DESCRIPTION (provided by applicant): We propose to expand the research focus of the Center for Cardiovascular Disease Prevention by hiring an independent faculty recruit trained in human genetics, who will have a joint appointment in the Departments of Medicine and Molecular and Human Genetics at Baylor College of Medicine, to perform research in two main areas that are directly relevant to improving prevention of coronary heart disease (CHD). He/she will establish effective tools for assessment and stratification of CHD risk based on genetic variation, mainly single nucleotide polymorphisms (SNPs). He/she will fully characterize known and novel genes and genomic regions that affect high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and CHD in a special subpopulation consisting of individuals in the upper and lower extremes for TG or HDL-C. The overall strategy of this approach has clear therapeutic goals: 1. Better accuracy of risk prediction and classification, based on the individual's genetic information, thus enabling more appropriate preventive treatment. 2. Identification of genes and genomic regions associated with HDL-C, TG, CHD risk, and response to commonly used drugs to treat lipid disorders. Achieving these goals will develop and extend inter- and intra-institutional collaborations that are already ongoing. Data from the largest prospective cohort studies in the United States-the Atherosclerosis Risk in Communities (ARIC), Candidate Gene Association Resource (CARE), and Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) studies-will be analyzed by the recruit in close collaboration with the Department of Molecular and Human Genetics at Baylor College of Medicine and the Human Genetics Center at The University of Texas School of Public Health to identify SNPs associated with low HDL-C, high TG, and CHD risk. Genes found by the association studies will be sequenced by the Human Genome Sequencing Center at Baylor College of Medicine in a population of patients with low HDL-C and high TG participating in a double-blind study of statin and fibrate therapy, to examine the association of sequence variations in the genes with HDL-C and TG levels, and to determine the influence of these genes on lipid changes in response to commonly used drugs. Genetic information will therefore be applied in an effort to refine CHD risk assessment and to improve risk reduction through personalized preventive therapy. Cardiovascular disease remains the leading cause of death and medical expenses in the United States. Prevention of cardiovascular disease can be improved by using recent genetic discoveries to identify who is at risk of developing a heart attack and by improved understanding of the genes that control the levels of fats (triglycerides and HDL ["good"] cholesterol) in blood.