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.
The aim of this research is to elucidate the genes that modulate hypertrophic cardiomyopathy (HCM) severity, so that comprehensive genetic screening will be possible as part of a goal to eliminate the sudden death caused by HCM. .
| Zhao, Wenyuan; Zhao, Tieqiang; Chen, Yuanjian et al. (2017) Differential Expression of Hypertensive Phenotypes in BXD Mouse Strains in Response to Angiotensin II. Am J Hypertens 31:108-114 |
