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物决定 基因，人们对此知之甚少。发现差异漏洞的遗传基础在 为HCM患者提供预测性和个性化护理，并将使更全面的遗传和 进行基因组筛查，以期尽早进行干预，消除猝死风险。这个 事实证明，发现导致HCM变异和不完全外显的修饰基因是困难的 在人类群体中。大型小鼠遗传参考种群(GRP)现在终于提供了一个有效的解决方案。 BXD品系是目前最大和特征最好的小鼠GRP家族，由160个高度 C57BL/6J(B6)和DBA/2J(D2)亲本株系杂交后代的不同品系。BXD 是专门用于系统遗传学研究的，使用经典的正向遗传学方法和 反向遗传研究。我们已经证明了D2-BXD杂交的父亲-是一种优秀的小鼠HCM 模特。D2含有MYBPC3和MyH7的突变，这两个基因是肥厚性心肌病的主要致病基因，以及 人间同种异构体。相比之下，B6(BXD的母亲)有野生型等位基因和正常的心脏。目标是 我们的建议之一是确定影响HCM表型严重程度的修饰基因。我们的假设是 修饰基因和因果基因的交互作用控制着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、分子和细胞分析。 这项工作将是变革性的，并将导致识别出强大的候选基因和网络 HCM表型的潜在个体差异。目标1：系统量化与HCM相关的特征 以及它们在100种BXD等位基因小鼠中的变异性和遗传力。目标1的目的是 确定100株BXD的临床、实验室和分子hcm表型，为我们奠定基础 在AIMS 2和AIMS 3中探索HCM的遗传变异、辅助因素和机制。目标2：定义 调节HCM的严重程度。基于目标1中生成的表型数据，以及已经 获得B6和D2以及BXD的序列和转录组数据，我们将识别出强大的基因变体 使用最先进的系统遗传策略和常规方法调节HCM表型的可变性 分子和细胞分析。目的3：验证小鼠HCM修饰基因候选基因的翻译有效性。 我们将用已建立的HCM人类GWAS数据来证明AIM 2中确定的候选基因。互惠的 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 在BXD中，变异与HCM相关的特征有关。将优先考虑的候选基因与 无论是小鼠还是人类的HCM研究，我们都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。我们将最终验证调控HCM的基因 使用损失功能策略的表型严重程度。

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.