Cardiac copper content and its relationship with heart physiology: Insights based on quantitative genetic and functional analyses using BXD family mice

Abstract

BackgroundCopper (Cu) is essential for the functioning of various enzymes involved in important cellular and physiological processes. Although critical for normal cardiac function, excessive accumulation, or deficiency of Cu in the myocardium is detrimental to the heart. Fluctuations in cardiac Cu content have been shown to cause cardiac pathologies and imbalance in systemic Cu metabolism. However, the genetic basis underlying cardiac Cu levels and their effects on heart traits remain to be understood. Representing the largest murine genetic reference population, BXD strains have been widely used to explore genotype-phenotype associations and identify quantitative trait loci (QTL) and candidate genes.MethodsCardiac Cu concentration and heart function in BXD strains were measured, followed by QTL mapping. The candidate genes modulating Cu homeostasis in mice hearts were identified using a multi-criteria scoring/filtering approach.ResultsSignificant correlations were identified between cardiac Cu concentration and left ventricular (LV) internal diameter and volumes at end-diastole and end-systole, demonstrating that the BXDs with higher cardiac Cu levels have larger LV chamber. Conversely, cardiac Cu levels negatively correlated with LV posterior wall thickness, suggesting that lower Cu concentration in the heart is associated with LV hypertrophy. Genetic mapping identified six QTLs containing a total of 217 genes, which were further narrowed down to 21 genes that showed a significant association with cardiac Cu content in mice. Among those, Prex1 and Irx3 are the strongest candidates involved in cardiac Cu modulation.ConclusionCardiac Cu level is significantly correlated with heart chamber size and hypertrophy phenotypes in BXD mice, while being regulated by multiple genes in several QTLs. Prex1 and Irx3 may be involved in modulating Cu metabolism and its downstream effects and warrant further experimental and functional validations.

Systems genetics identifies methionine as a high risk factor for Alzheimer's disease

“…In this study, we integrated phenotypic resources from the BXD panel, including more than 300 neural phenotypes from over 150 mouse strains. The recombinant inbred population of the BXD family, as one of the largest and well-characterized genetic reference populations, is the basis for studying various diseases, such as cancer, cognitive disorders, and heart diseases (Zhu et al, 2020 ; Bajpai et al, 2023 ; Zhou et al, 2023 ; Xu et al, 2024 ). The correlation of the BXD RI family has been extended to genetic analysis of behavioral phenotypes, including drug addiction, neurodegenerative processes, etc.…”

Comprehensive analysis of geographic and breed-purpose influences on genetic diversity and inherited disease risk in the Doberman dog breed

“…According to the Genecards resource [ 23 ] CES1 has a demonstrated role in cardiac conduction and cardiac drug metabolism while IRX6 is a potential hub gene in the pathogenesis of heart failure [ 24 ]. IRX3 is potential modulator of cardiac copper metabolism [ 25 ]. On CFA3, the gene MAN2B2 in Doberman populations contains two potentially damaging missense variants that are very rare in the general dog population.…”