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，以发展独立的转化研究者的职业生涯，重点研究二尖瓣脱垂（MVP）的遗传学及其进展。主要研究者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的研究，并在马萨诸塞州总医院（MGH）完成了超声心动图的研究。该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备（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）和瓣膜病/超声心动图专家（Manning博士和Levine博士）。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。虽然MVP是孤立性二尖瓣反流（MR）最常见的原因，需要手术修复，但对MVP的遗传决定因素及其进展知之甚少。到目前为止，常染色体显性MVP的3个位点已经在染色体11,16和13上被描述，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%，但家庭MVP的患病率尚不清楚。在13号染色体家族中，先前的非诊断形态通常代表基因携带者表达的早期阶段，并且具有完全诊断性MVP的两个显著特征：前移位的融合点和后小叶不对称。本研究验证了FHS群体存在早期MVP并可发展的假设，以及MVP遗传率高的假设。此外，通过多中心GWAS可以识别多个MVP位点。为了验证这些假设，候选人将：1)在基线和11-17年（FHS）和5年（BIDMC）的可用随访期间，通过超声心动图测量FHS后代队列和医院样本（BIDMC）的二尖瓣小叶覆盖高度、位移、厚度和MR程度。2)评估父母在后代队列中有MVP的第三代个体是否存在MVP。高MVP遗传率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的家庭成员进行常规筛查。3)使用GWAS在FHS和其他美国和欧洲队列（约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理解社区MVP患者进展和临床结果的可变性的关键步骤，具有开发早期预防进展的治疗靶点的潜力。

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.