Background: Cardiac fibrosis is a common pathology in the diseased heart, which can cause a loss of elasticity and contractile dysfunction. Cardiac fibrosis is a complex process driven by many pathological triggers which involve numerous genes, pathways and cell types. Despite its importance, the genetic basis for the development of cardiac fibrosis has not been systematically explored.
Methods and Results: We have developed a resource, the Hybrid Mouse Diversity Panel (HMDP) for high resolution GWAS and systems genetics study of quantitative traits in mice. Eight week old female mice from 80 unique inbred strains of the HMDP were given 30 ug/g/day of isoproterenol (ISO) for three weeks and cardiac fibrosis was assessed by Masson Trichrome staining which revealed a wide spectrum in the degree of fibrosis among the HMDP strains both before and after treatment. Using the Efficient Mixed Model Algorithm, we identified 13 significant or suggestive loci contributing to cardiac fibrosis, many containing numerous gene candidates. Within one of these loci, Abcc6, an orphan ABC transporter linked to the human disease pseudoxanthoma elasticum, was identified as a possible candidate for ISO-induced cardiac fibrosis. A splice-site mutation present in 19 strains of the HMDP was significantly linked to a higher degree of ISO-induced cardiac fibrosis(P=1E-4) but was not linked to increased fibrosis in untreated animals(P=0.25). Targeted genetic knockout of Abcc6 promoted ISO-induced cardiac fibrosis while reintroducing the wildtype Abcc6 allele to an genetic strain homozygous for the Abcc6 splice site mutation significantly alleviated ISO-induced cardiac fibrosis.
Conclusion: A GWAS performed on levels of cardiac fibrosis observed in ISO treated animals using HMDP mice as model system uncovered significant genetic contributions to stress-induced cardiac fibrosis. Abcc6 is a novel gene contributing to ISO-induced cardiac fibrosis in the heart.