Journal
NATURE GENETICS
Volume 40, Issue 5, Pages 529-537Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.129
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Funding
- Medical Research Council [MC_U120085815] Funding Source: researchfish
- MRC [MC_U120085815] Funding Source: UKRI
- British Heart Foundation Funding Source: Medline
- Medical Research Council [MC_U120085815] Funding Source: Medline
- NIEHS NIH HHS [R37 ES02710, R37 ES002710] Funding Source: Medline
- Department of Health Funding Source: Medline
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We aimed to identify genetic variants associated with heart failure by using a rat model of the human disease. We performed invasive cardiac hemodynamic measurements in F-2 crosses between spontaneously hypertensive heart failure ( SHHF) rats and reference strains. We combined linkage analyses with genome-wide expression profiling and identified Ephx2 as a heart failure susceptibility gene in SHHF rats. Specifically, we found that cis variation at Ephx2 segregated with heart failure and with increased transcript expression, protein expression and enzyme activity, leading to a more rapid hydrolysis of cardioprotective epoxyeicosatrienoic acids. To confirm our results, we tested the role of Ephx2 in heart failure using knockout mice. Ephx2 gene ablation protected from pressure overload-induced heart failure and cardiac arrhythmias. We further demonstrated differential regulation of EPHX2 in human heart failure, suggesting a cross-species role for Ephx2 in this complex disease.
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