Refined mapping of a hypertension susceptibility locus on rat chromosome 12

Sasha Z. Prisco, Jeremy W. Prokop, Allison B. Sarkis, Nan Cher Yeo, Matthew J. Hoffman, Colin C. Hansen, Howard J. Jacob, Michael J. Flister, Jozef Lazar

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Previously, we found that transferring 6.1 Mb of salt-sensitive (SS) chromosome 12 (13.4-19.5 Mb) onto the consomic SS-12BN 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-12BN consomic, the 830-kb blood pressure locus was associated with a Δ+15 mm Hg (P<0.01) increase in blood pressure, which coincided with elevated albuminuria (Δ+32 mg/d; P<0.001), proteinuria (Δ+48 mg/d; P<0.01), protein casting (Δ+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-12BN congenic strain may be translated to a better understanding of human hypertension.

Original languageEnglish (US)
Pages (from-to)883-890
Number of pages8
JournalHypertension
Volume64
Issue number4
DOIs
StatePublished - 2014

Keywords

  • Hypertension
  • Inbred BN
  • Inbred Dahl
  • Rats
  • Rats

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