Cardiac pathways distinguish two epistatic modules enacting BP quantitative trait loci and candidate gene analysis

Animal models emulating essential hypertension are an informative means by which to elucidate the physiological mechanisms and gene-gene interactions underlying blood pressure (BP) regulation. We have localized earlier quantitative trait loci (QTLs) for BP on Chromosome (Chr) 2 of Dahl salt-sensitive (DSS) rats, but their chromosome delineations were too large for gene identification. To advance toward positional cloning of these QTLs, we constructed congenic strains that systematically dissect a Chr 2 segment with no overlaps. BP and cardiac functions were measured by telemetry and echocardiography. Six QTLs were delimited, each independently influencing BP. The intervals lodging two of them harbor 10-15 genes and undefined loci. These six QTLs can be grouped into two epistatic modules distinguishable by cardiac pathways/cascades. None of the genes known to exert physiological effects on BP in the segments harboring the six QTLs are leading candidates, as their protein products are the same in DSS rats and similar to those in their Milan normotensive counterparts. Specifically, the lack of an amino-acid alteration, coupled with a lack of difference in the alpha1-Na-K-ATPase activity, excluded ATPase, Na+/K+-transporting, alpha-1 polypeptide as a candidate gene for C2QTL6. The identification of the six QTLs will likely develop into a novel diagnostic and/or therapeutic target for essential hypertension and hypertension-associated diseases.