Refined Mapping of a Hypertension Susceptibility Locus on Rat Chromosome 12

Abstract

Previously, we found that transferring 6.1 Mb of salt-sensitive (SS) chromosome 12 (13.4–19.5 Mb) onto the consomic SS-12 BN background significantly elevated mean arterial pressure in response to an 8% NaCl diet (178±7 versus 144±2 mm Hg; P <0.001). Using congenic mapping, we have now narrowed the blood pressure locus by 86% from a 6.1-Mb region containing 133 genes to an 830-kb region (chr12:14.36–15.19 Mb) with 14 genes. Compared with the SS-12 BN consomic, the 830-kb blood pressure locus was associated with a ∆+15 mm Hg ( P <0.01) increase in blood pressure, which coincided with elevated albuminuria (∆+32 mg/d; P <0.001), proteinuria (∆+48 mg/d; P <0.01), protein casting (∆+154%; P <0.05), and renal fibrosis (∆+79%; P <0.05). Of the 14 genes residing in the 830-kb locus, 8 were differentially expressed, and among these, Chst12 (carbohydrate chondroitin 4 sulfotransferase 12) was most consistently downregulated by 2.6- to 4.5-fold ( P <0.05) in both the renal medulla and cortex under normotensive and hypertensive conditions. Moreover, whole genome sequence analysis of overlapping blood pressure loci revealed an ≈86-kb region (chr12:14 541 567–14 627 442 bp) containing single-nucleotide variants near Chst12 that are unique to the hypertensive SS strain when compared with the normotensive Brown Norway, Dahl salt-resistant, and Wistar-Kyoto strains. Finally, the 830-kb interval is syntenic to a region on human chromosome 7 that has been genetically linked to blood pressure, suggesting that insight gained from our SS-12 BN congenic strain may be translated to a better understanding of human hypertension.