Genetic Determinants and Progression of Mitral Valve Prolapse

二尖瓣脱垂的遗传决定因素和进展

• 批准号: 8635682
• 负责人: Francesca N Delling
• 金额: $ 12.71万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-17 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635682
• 关键词: Address; Boston; Cardiac; Cardiology; Cardiovascular system; Chromosomes; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 13; Clinical; Clinical effectiveness; Communities; Data; Development; Diagnosis; Diagnostic; Discipline; Disease; Disease Progression; Echocardiography; European; Family; Family member; Fellowship; Fostering; Foundations; Framingham Heart Study; France; Future; General Hospitals; General Population; Generations; Genes; Genetic; Genetic Determinism; Genotype; Goals; Height; Heritability; Heterogeneity; Hospitals; Image; Image Analysis; Individual; International; Intervention; Israel; Knowledge; Laboratories; Lead; Left; Left atrial structure; Link; Maps; Marfan Syndrome; Massachusetts; Master of Public Health; Measurement; Measures; Medical center; Medicine; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Mitral Valve Insufficiency; Mitral Valve Prolapse; Modeling; Molecular Genetics; Morphology; Operative Surgical Procedures; Outcome; Parents; Patients; Population; Prevalence; Public Health Schools; Research; Research Personnel; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Staging; Testing; Thick; Time; Training; Work; base; career; clinical epidemiology; cohort; exome; experience; filamin; follow-up; genetic epidemiology; genetic linkage analysis; genome wide association study; genome-wide; multidisciplinary; non-invasive imaging; offspring; population based; prevent; public health relevance; repaired; screening; skills; success; therapeutic target

DESCRIPTION (provided by applicant): The K23 Award will support rigorous training for the development of a career as an independent translational investigator with a focus on the genetics of mitral valve prolapse (MVP) and its progression. The principle investigator has completed a fellowship in cardiology and advanced imaging at Beth Israel Deaconess Medical Center (BIMDC) and a fellowship in echocardiography at Massachusetts General Hospital (MGH). The candidate has gained expertise in linkage analysis studies and phenotypic-genotypic correlations. As a staff cardiologist at BIDMC, she is now seeking new skills in genetic epidemiology and genome-wide association studies (GWAS). She will have access to a state-of-the-art genotyping facility (FHS), and echocardiography laboratories (BIDMC and FHS). Her multidisciplinary mentoring team includes experts in GWAS (Dr Ramachandran), and valvular disease/echocardiography (Drs Manning and Levine). A Master of Public Health in Clinical Effectiveness (Harvard School of Public Health) will provide the coursework necessary for her academic success. Although MVP is the most common cause of isolated mitral regurgitation (MR) requiring surgical repair, little is known about the genetic determinants of MVP and its progression. To date, 3 loci for autosomal dominant MVP have been described on chromosomes 11, 16 and 13, but gene finding has proved elusive. In addition, while the prevalence of MVP in the community is 2-5%, the prevalence of familial MVP is unknown. In the chromosome 13 family, previously non-diagnostic morphologies often represent early stages of expression in gene carriers and share two salient features with fully diagnostic MVP: an anteriorly displaced coaptation point and posterior leaflet asymmetry. This proposal tests the hypotheses that early stages of MVP exist and can progress in the FHS community, and that MVP heritability is high. In addition, several MVP loci can be identified through a multicenter GWAS. To test these hypotheses, the candidate will: 1) Measure mitral leaflet coaptation height, displacement, thickness, and degree of MR by echocardiography in the FHS Offspring Cohort and in a hospital-based sample (BIDMC) at baseline and at available follow-up of 11-17 (FHS) and 5 years (BIDMC). 2) Evaluate the presence of MVP in Gen 3 individuals whose parents in the Offspring Cohort have MVP. High MVP heritability would lead to specific gene-finding strategies such as whole-exome analysis and clarify if routine screening of family members in the community is warranted. 3) Search for MVP loci using GWAS both in FHS and in other US and European cohorts (> 2500 MVP subjects) (Leducq MITRAL Network). These aims represent crucial steps towards future gene-finding strategies and understanding of the variability of progression and clinical outcomes among MVP patients in the community, with the potential of developing therapeutic targets to prevent progression at an early stage.

描述（由申请人提供）：K23 奖将支持作为独立转化研究者的职业发展的严格培训，重点关注二尖瓣脱垂 (MVP) 的遗传学及其进展。主要研究者已在贝斯以色列女执事医疗中心 (BIMDC) 完成了心脏病学和高级成像研究，并在马萨诸塞州总医院 (MGH) 完成了超声心动图研究。候选人已获得连锁分析研究和表型-基因型相关性方面的专业知识。作为 BIDMC 的一名心脏病专家，她现在正在寻求遗传流行病学和全基因组关联研究 (GWAS) 方面的新技能。她将可以使用最先进的基因分型设施 (FHS) 和超声心动图实验室（BIDMC 和 FHS）。她的多学科指导团队包括 GWAS 专家（Ramachandran 博士）和瓣膜疾病/超声心动图专家（Manning 和 Levine 博士）。临床有效性公共卫生硕士（哈佛大学公共卫生学院）将为她提供学术成功所需的课程。尽管 MVP 是需要手术修复的孤立性二尖瓣反流 (MR) 的最常见原因，但人们对 MVP 及其进展的遗传决定因素知之甚少。迄今为止，常染色体显性 MVP 的 3 个基因座已在 11、16 和 13 号染色体上被描述，但基因发现却难以捉摸。此外，虽然社区 MVP 的患病率为 2-5%，但家族 MVP 的患病率尚不清楚。在 13 号染色体家族中，以前的非诊断性形态通常代表基因载体表达的早期阶段，并且与完全诊断性 MVP 具有两个显着特征：接合点前移和后叶不对称。该提案测试了以下假设：MVP 的早期阶段存在并且可以在 FHS 社区中取得进展，并且 MVP 遗传力很高。此外，可以通过多中心 GWAS 识别多个 MVP 位点。为了测试这些假设，考生将： 1) 在基线和可用的随访中通过超声心动图测量 FHS 后代队列和医院样本 (BIDMC) 的二尖瓣贴合高度、位移、厚度和 MR 程度11-17 岁 (FHS) 和 5 年 (BIDMC)。 2) 评估后代队列中父母拥有 MVP 的第 3 代个体中 MVP 的存在情况。高 MVP 遗传力将导致特定的基因发现策略，例如全外显子组分析，并澄清是否有必要对社区中的家庭成员进行常规筛查。 3) 使用 GWAS 在 FHS 以及其他美国和欧洲队列（> 2500 名 MVP 受试者）中搜索 MVP 位点（Leducq MITRAL 网络）。这些目标代表了未来基因发现策略和了解社区 MVP 患者进展和临床结果变异性的关键步骤，并有可能开发治疗靶点以在早期阶段预防进展。