Identification of Hypertension Susceptibility Loci on Rat Chromosome 12

Abstract

Previous studies have identified multiple blood pressure and renal disease quantitative trait loci located on rat chromosome 12. In the present study, we narrowed blood pressure loci using a series of overlapping Dahl salt-sensitive/Mcwi (SS)-12 Brown Norway (BN) congenic lines. We found that transferring 6.1 Mb of SS chromosome 12 (13.4-19.5 Mb) onto the consomic SS-12BN background significantly elevated blood pressure on 1% NaCl (146±6 versus 127±1 mm Hg; P<0.001) and 8% NaCl diets (178±7 versus 144±2 mm Hg; P<0.001). Compared with the SS-12BN consomic, these animals also had significantly elevated albumin (218±31 versus 104±8 mg/d; P<0.001) and protein excretion (347±41 versus 195±12 mg/d; P<0.001) on a 1% NaCl diet. Elevated blood pressure, albuminuria, and proteinuria coincided with greater renal and cardiac damage, demonstrating that SS allele(s) within the 6.1 Mb congenic interval are associated with strong cardiovascular disease phenotypes. Sequence analysis of the 6.1 Mb congenic region revealed 12 673 single nucleotide polymorphisms between SS and BN rats. Of these polymorphisms, 293 lie within coding regions, and 18 resulted in nonsynonymous changes in conserved genes, of which 5 were predicted to be potentially damaging to protein function. Syntenic regions in human chromosome 7 have also been identified in multiple linkage and association studies of cardiovascular disease, suggesting that genetic variants underlying cardiovascular phenotypes in this congenic strain can likely be translated to a better understanding of human hypertension.