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

脂质的全基因组序列解释，以发现冠状动脉疾病的新基因和机制

基本信息

批准号：
10722515
负责人：
Satoshi Koyama
金额：
$ 16.5万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722515
关键词：
Address Age All of Us Research Program Alleles Applied Skills Atherosclerosis Biological Assay Boston Cardiology Cardiovascular Diseases Cause of Death Cholesterol Clinical Cloud Computing Code Collaborations Complex Coronary Arteriosclerosis Data Data Set Dedications Diagnosis Diagnostic Diagnostic Sensitivity Disease Disease-Free Survival Early Diagnosis Early Intervention Early treatment Exposure to Familial Hypercholesterolemia Family General Hospitals Generations Genes Genetic Genetic Research Genetic Risk Genetic Screening Genomic medicine Genomics Genotype Guidelines Hand Healthcare Heritability Human Genetics Hyperlipidemia In Vitro Individual Inherited Institution Investigation Investments Knowledge LDL Cholesterol Lipoproteins Lipids Machine Learning Massachusetts Mentors Mentorship Methods Modeling Molecular Biology Molecular Diagnosis Mutagenesis Mutation National Heart, Lung, and Blood Institute Pathogenesis Persons Phase Physicians Population Prevention Preventive Principal Investigator Recommendation Research Research Personnel Resources Risk Risk Factors Scientist Statistical Methods Technical Expertise Therapeutic Trans-Omics for Precision Medicine United States Department of Veterans Affairs United States National Institutes of Health Untranslated RNA Update Variant Veterans biobank causal variant cohort data access data handling diagnostic criteria disorder prevention exome exome sequencing experience family management genetic analysis genetic disorder diagnosis genetic epidemiology genetic predictors genetic testing genetic variant genome sequencing genome-wide high risk population hypercholesterolemia improved in silico insight machine learning method mutation carrier novel novel diagnostics polygenic risk score precision medicine premature prevent programs risk prediction risk stratification risk variant skills trait translational genomics whole genome

项目摘要

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.

项目概要/摘要冠状动脉疾病（CAD）是全世界家庭高胆固醇血症的主要原因之一。 (FH) 是遗传性高胆固醇血症的一种极端情况，也是 CAD 的重要危险因素。由已知的胆固醇相关基因的单一突变引起，这些突变的携带者会暴露在严重的环境中早期干预已被证明可以减少高胆固醇血症和 CAD 的发生。因此，早期诊断和治疗是预防动脉粥样硬化进展并延长无 CAD 生存期的关键。在 FH 的管理中具有重要意义。目前的指南建议对重症患者进行基因筛查和基于基因型的风险分层然而，目前的遗传诊断标准仅限于高胆固醇血症。已经描述过的基因/变体。最近的研究（包括我们的研究）表明，FH 基因检测的诊断率有限（< 2% 患有严重高胆固醇血症的个体）此外，只有约 2% 具有类似的强多基因。尽管研究表明遗传学对 FH 有相当大的贡献，但从这些发现来看，Dr. Koyama 认为存在未被发现的 FH 等位基因，并且可能对诊断、监测和治疗很重要。旨在提高 FH 的基因诊断率并捕获目前潜在的携带者。由于尚未确诊，小山博士建议使用人口规模制定更新的 FH 诊断标准基因组序列队列和综合变异解释框架。在此提案中，首先，Koyama 博士将通过关联超罕见的 FH 相关变异/基因来完善 FH 相关变异/基因列表。其次，Koyama 博士将分析扩展到非编码。使用全基因组测序的当前诊断标准中未赋予的变异最后，小山博士将整合常见和罕见的遗传风险分层模型来全面描述高脂血症的遗传风险。该项目建立在小山博士的临床/研究技能和经验的基础上，使他能够获得更多在主要导师Dr.的指导下，拥有丰富的心血管疾病基因研究经验。 Pradeep Natarajan，预防心脏病学主任，联合导师 Patrick Ellinor 博士，首席马萨诸塞州总医院的心脏病科小山博士将大大受益于丰富的科学知识麻省理工学院和哈佛大学布罗德研究所以及心脏病学部的资源和合作马萨诸塞州总医院。