Genetic Modulation of Hypertrophic Cardiomyopathy Severity

肥厚型心肌病（HCM）临床表现的变异性主要由修饰语决定 基因，我们对此知之甚少。发现不同脆弱性的遗传基础对于 为HCM患者提供预测性和个性化的护理，并将使更全面的遗传和 基因组筛查，目的是尽早干预，消除猝死风险。的 发现导致HCM变异和不完全转化的修饰基因已被证明是困难的 在人类队列中。大型鼠遗传参考群体（GRP）现在终于提供了一个有效的解决方案。 BXD家族的菌株-目前最大和最好的表征小鼠GRP-由160个高度 C57BL/6J（B6）和DBA/2J（D2）亲本品系杂交后代的不同品系。BXD 已经培育了专门用于系统遗传学研究，使用经典的正向遗传学方法和 逆转基因研究我们已经证明了BXD杂交的D2-父亲是一种极好的鼠HCM 模型D2含有Mybpc3和Myh7的突变，这是HCM的主要致病基因，也是HCM的关键特征。 人HCM。相反，B6（BXDs的母亲）具有野生型等位基因和正常的心脏。客观 我们的建议是确定修饰基因，影响HCM表型的严重程度。我们的假设是 修饰基因和致病基因的相互作用控制HCM的严重程度和相关表型。这里的研究 涉及B6、D2和多达100个BXD的多尺度遗传、转录组学、分子和细胞分析。 这项工作将是变革性的，并导致确定强有力的候选基因和网络 HCM表型的潜在个体差异。目的1：系统地量化HCM相关性状 以及它们在100个BXD基因型的同基因小鼠中的变异性和遗传性。目标1的目的是 确定100个BXD菌株的临床、实验室和分子HCM表型，为我们奠定基础。 探索HCM的遗传变异、辅助因子和机制，目的2和3。目标2：定义基因， 调节HCM的严重程度。基于Aim 1中生成的表型数据，以及已经建立的 获得了B6和D2以及BXD的序列和转录组数据，我们将鉴定出 使用最先进的系统遗传策略和常规方法调节HCM表型的变异性 分子和细胞分析。目的3：检测小鼠HCM修饰基因候选基因的翻译效度。 我们将证明目标2中确定的候选基因与已建立的HCM人GWAS数据。以往复 反向翻译，我们将评估来自人类队列的候选HCM基因，并确定这些基因是否 变异体与BXD中的HCM相关性状相关。将来自不同基因组的最高优先级候选基因 无论是小鼠和人类HCM研究，我们将产生易感的分子和统计模型， 候选基因、连锁表型和相关机制。我们将最终验证基因调节HCM 表型严重程度使用功能丧失策略。

Variability in hypertrophic cardiomyopathy (HCM) clinical manifestation is primarily determined by modifier genes, which are poorly understood. Discovering of the genetic basis of differential vulnerability is critical in predictive and personalized care for patients with HCM and will enabling more comprehensive genetic and genomic screening with an aim to intervene as early as possible and eliminate risk of sudden death. The discovery of modifier genes that contribute to variation and incomplete penetrance of HCM has proven difficult in human cohorts. Large murine genetic reference populations (GRPs) now finally provide a effective solution. The BXD family of strains—currently the largest and best characterized mouse GRP—is made up of 160 highly diverse lines that descend from crosses between C57BL/6J (B6) and DBA/2J (D2) parental strains. The BXDs have been bred specifically for systems genetics studies using both classic forward genetic methods and for reverse genetic studies. We have shown that the D2—father of the BXD cross—is an excellent murine HCM model. D2 contains mutations of Mybpc3 and Myh7, the major causal genes of HCM and the key features of human HCM. In contrast, the B6 (mother of the BXDs) has wild type alleles and normal hearts. The objective of our proposal is to identify modifier genes that affect the severity of HCM phenotypes. Our hypothesis is that interactions of modifier and causal genes govern HCM severity and related phenotypes. The research here involves multi-scale genetic, transcriptomic, molecular and cellular profiling of B6, D2, and up to 100 BXDs. This work will be transformative and lead to the identification of strong candidate genes and networks underlying individual differences in HCM phenotypes. Aim 1: Systematically quantify HCM-associated traits and their variability and heritability across 100 BXD genotypes of isogenic mice. The purpose of Aim 1 is to determine the clinical, laboratory and molecular HCM phenotypes in 100 BXD strains, setting the stage for us to explore genetic variation, cofactors, and mechanisms of HCM in Aims 2 and 3. Aim 2: Define genes that modulate the severity of HCM. Building upon the phenotype data generated in Aim 1, as well as the already acquired sequence and transcriptome data for B6 and D2, and BXDs, we will identify strong gene variants that modulate variability of HCM phenotypes using state-of-the-art system genetic strategies and conventional molecular and cellular assays. Aim 3: Test the translational validity of mouse HCM modifier gene candidates. We will justify candidate genes identified in Aim 2 with established HCM human GWAS data. In reciprocal reverse translation, we will evaluate candidate HCM genes from human cohorts and determine whether these variants are associated with HCM-associated traits in BXDs. Combining the top priority gene candidates from both mouse and human HCM studies, we will generate molecular and statistical models of susceptible candidate genes, linked phenotypes, and relevant mechanisms. We will finally validate genes modulating HCM phenotype severity using loss-off function strategy.