Cardiac phenotyping in the BXD strains as a genetic reference population for cardiovascular diseases
Authors: Munkhsaikhan Undral , Sabau Ramona , Alberson Neely , Towbin Jeffrey A. , Lu Lu , Purevjav Enkhsaikhan 
Published: June 2021

Introduction

Discovery of genetic modifiers in cardiomyopathy (CM) has proved difficult in human cohorts because the wide range of clinical manifestations due to joint effects of causal and multiple modifier genes and environment. Therefore, combining human GWAS findings with additional animal model and molecular data using systems genetics is powerful approach to understand complex diseases by focusing on how genes work together in groups rather than singly. The main challenge for a systems genetics analysis is the need for comparatively large sample sizes drawn from a genetic reference population (GRP) and the use of advanced statistical and computational methods and models. The study was aimed to establish a murine GRP for CM systems genetics analysis. The BXD recombinant inbred (RI) strains derived from C57BL/6J and DBA/2J (D2) mice is the largest murine GRP. The parental D2 strain expresses CM key features, which make BXD strains particularly suited for systems genetics analysis for CMs.

Hypothesis

BXD strains can be used to study genetic influences and modifiers in CMs.

Methods

CM‐associated traits (heart function, rhythm and mass, cardiomyocyte size, fibrosis) and heart transcriptome were assessed in male and female BXD RI mice (40 lines, N>5) at 5–6 months of age. Echocardiography, ECG and blood pressure was performed followed by cardiac histology and microarray analysis (Affymetrix Mouse Gene 2.0 ST).

Results

Echocardiography revealed more than two‐fold variance in LV end‐systolic and end‐diastolic volumes among tested BXD strains. BXD155 has the largest end‐systolic LV volume (42.8±9.0 μl) and BXD74 has the smallest volume (12.1±4.8 μl). Accordingly, %EF also varied greatly among BXDs. Severe hypertension was found in many BXD strains with highest systolic and diastolic blood pressure (200/159 mmHg) in D2. Atrioventricular (AV) block, bradycardia, ST elevation, and inverted T wave was revealed in several BXD lines. The lowest heart rate was found in BXD171 mice (369±20 beat/min). Heart weight, cardiomyocyte size, and cardiac collagen volume fraction significantly varied among BXD strains as well. D2 strain has the largest hearts (185.1 mg) and B6 has the smallest hearts (129.8 mg), while the average heart weight among BXD strains is 144.7mg. Several CM causal and candidate genes such as Mybpc3, Prkag2, Ankrd1, Myl3, and Mypn have mutation in D2 mouse or they are trans‐regulated by the gene with mutation in D2.

Conclusions

CM phenotypes from D2 mouse are segregated among the BXD family of strains and CM‐associated traits vary among BXD strains, demonstrating that the BXD family as an excellent platform to identify genetic factors and modifiers that influence CM phenotypes. Identification of these factors will facilitate improved understanding of gene modifications and phenotypes in human CMs.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.