Genetic Determinants and Progression of Mitral Valve Prolapse

描述（由申请人提供）：K23奖将支持严格的培训，以发展作为独立翻译研究者的职业生涯，重点是二尖瓣脱垂（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）完成心脏病学和高级成像研究金，并在马萨诸塞州总医院（MGH）完成超声心动图研究金。候选人在连锁分析研究和表型-基因型相关性方面获得了专业知识。作为BIDMC的心脏病专家，她现在正在寻求遗传流行病学和全基因组关联研究（GWAS）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（Ramachandran博士）和瓣膜疾病/超声心动图（Manning和Levine博士）的专家。临床有效性公共卫生硕士（哈佛公共卫生学院）将为她的学术成功提供必要的课程。尽管MVP是需要手术修复的孤立性二尖瓣返流（MR）的最常见原因，但对MVP及其进展的遗传决定因素知之甚少。迄今为止，已在11、16和13号染色体上描述了常染色体显性MVP的3个位点，但基因发现被证明是难以捉摸的。此外，虽然社区MVP的患病率为2- 5%，但家族性MVP的患病率尚不清楚。在13号染色体家族中，以前非诊断性形态通常代表基因携带者表达的早期阶段，并与完全诊断性MVP共享两个显著特征：前移位接合点和后叶不对称。这项建议测试的假设，MVP的早期阶段存在，并可以在FHS社区的进展，MVP的遗传率很高。此外，通过多中心GWAS可以鉴定几个MVP基因座。为了检验这些假设，候选人将：1）在基线和11-17年（FHS）和5年（BIDMC）的可用随访时，通过超声心动图测量FHS后代队列和医院样本（BIDMC）的二尖瓣瓣叶接合高度、位移、厚度和二尖瓣返流程度。2)评估后代队列中父母患有MVP的第三代个体是否存在MVP。高MVP遗传性将导致特定的基因发现策略，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)在FHS和其他美国和欧洲队列（> 2500名MVP受试者）中使用GWAS搜索MVP基因座（Leducq MIPONS Network）。这些目标代表了未来基因发现策略的关键步骤，以及对社区MVP患者进展和临床结局变异性的理解，并有可能开发治疗靶点以预防早期进展。

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.