Whole genome sequence interpretation for lipids to discover new genes and mechanisms for coronary artery disease

项目摘要/摘要 冠心病(CAD)是世界范围内主要的死亡原因之一。家族性高胆固醇血症 (FH)是遗传性高胆固醇血症的极端病例，也是冠心病的重要危险因素。FH是由 通过已知胆固醇相关基因的单一突变，这些突变的携带者暴露在严重的 高胆固醇血症，并在幼年时发展为冠心病。早期干预已被证明可以减少 动脉粥样硬化的进展和延长无冠心病生存期。因此，早期诊断和治疗是必要的。 在FH的管理中很重要。 目前的指南建议对重症患者进行基因筛查和基于基因的风险分层 高胆固醇血症，以及特定的治疗方法。然而，目前的遗传诊断标准仅限于 已经描述过的基因/变种。 最近的研究，包括我们的研究，表明FH基因检测的诊断效率是有限的(&lt；2% 严重高胆固醇血症患者)。此外，只有~2%的人具有类似强的多基因 尽管研究表明遗传学对FH有相当大的贡献，但仍有贡献。从这些发现中，Dr。 小山假设存在未被发现的FH等位基因，并可能对诊断、监测和 治疗。目的是提高FH的遗传诊断产量并捕获当前潜在的携带者 未确诊的小山博士建议使用人口规模来制定FH的最新诊断标准 基因组序列队列和全面的变异解释框架。 在这项提案中，首先，小山博士将通过将超强辐射与FH相关的变异/基因列表进行细化 编码整个外显子组数据集中的变体。其次，小山博士将把分析扩展到非编码 使用全基因组测序的当前诊断标准中未授予的变异 数据集。最后，小山博士将整合常见和罕见的遗传风险分层模型，以 全面描述高脂血症的遗传风险。 这个项目建立在小山医生的临床/研究技能和经验的基础上，并使他能够获得更多 心血管疾病的遗传学研究经验。在初级导师Dr。 预防心脏病学主任兼共同导师帕特里克·埃利诺博士，预防心脏病学主任 马萨诸塞州综合医院的心脏病学，小山博士将从丰富的科学知识中受益匪浅 麻省理工学院和哈佛大学博德研究所的资源和合作 麻省总医院。

PROJECT SUMMARY/ABSTRACT Coronary artery disease (CAD) is one of the leading causes of death worldwide. Family hypercholesterolemia (FH) is an extreme case of inherited hypercholesterolemia and an important risk factor for CAD. FH is caused by a single mutation in known cholesterol-related genes, and carriers of these mutations are exposed to severe hypercholesterolemia and develop CAD at an early age. Early intervention has been shown to reduce the progression of atherosclerosis and prolong CAD-free survival. Therefore, early diagnosis and treatment are important in the management of FH. Current guidelines recommend genetic screening and genotype-based risk stratification for people with severe hypercholesterolemia, as well as specific therapies. However, current genetic diagnostic criteria are limited to genes/variants that have already been described. Recent investigations, including ours, suggest that the diagnostic yield of genetic testing for FH is limited (< 2% of individuals with severe hypercholesterolemia). Furthermore, only ~2% have a similarly strong polygenic contribution despite studies indicating a sizable contribution of genetics to FH. From these findings, Dr. Koyama hypothesize that undiscovered FH alleles exist and may be important for diagnosis, surveillance, and treatment. With the aim of improving genetic diagnostic yields for FH and capturing potential carriers currently undiagnosed, Dr. Koyama proposes to develop an updated diagnostic criteria of FH using the population-scale genome sequence cohorts and comprehensive variant interpretation framework. In this proposal, first, Dr. Koyama will refine the list of FH associated variants/genes by associating ultrarare coding variants in the whole exome datasets. Second, Dr. Koyama will extend the analysis to the noncoding variants which were not conferred in the current diagnostic criteria using the whole genome sequencing dataset. Finally, Dr. Koyama will integrate common and rare genetic risk stratification models to comprehensively describe the genetic risk of hyperlipidemia. This project is built on Dr. Koyama’s clinical/research skills and experiences and allows him to gain more experience in genetic research in the cardiovascular disease. Under the mentorship of primary mentor Dr. Pradeep Natarajan, the Director of Preventive Cardiology and co-mentor Dr. Patrick Ellinor, the Chief of Cardiology of Massachusetts General Hospital, Dr. Koyama will significantly benefit from rich scientific resources and collaborations at the Broad Institute of MIT and Harvard and at the Division of Cardiology at the Massachusetts General Hospital.