Faculty Collaboration Database

Refined mapping of a hypertension susceptibility locus on rat chromosome 12. Hypertension 2014 Oct;64(4):883-90

Date

07/09/2014

Pubmed ID

25001272

Pubmed Central ID

PMC4162822

DOI

10.1161/HYPERTENSIONAHA.114.03550

Scopus ID

2-s2.0-84914703209 (requires institutional sign-in at Scopus site)   7 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-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.

Author List

Prisco SZ, Prokop JW, Sarkis AB, Yeo NC, Hoffman MJ, Hansen CC, Jacob HJ, Flister MJ, Lazar J

MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Chromosome Mapping
Chromosomes, Human, Pair 7
Chromosomes, Mammalian
Gene Expression
Genetic Predisposition to Disease
Humans
Hypertension
Kidney Cortex
Kidney Medulla
Rats
Rats, Inbred BN
Rats, Inbred Dahl
Rats, Inbred WKY
Reverse Transcriptase Polymerase Chain Reaction
Sodium Chloride, Dietary
Synteny