title: 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.
authors.affiliation: From the Human and Molecular Genetics Center (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., C.C.H., H.J.J., M.J.F., J.L.) and Departments of Physiology (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., H.J.J., M.J.F., J.L.), Pediatrics (H.J.J.), and Dermatology (J.L.), Medical College of Wisconsin, Milwaukee.
authors.forename: Sasha Z
authors.initials: SZ
authors.lastname: Prisco
authors.affiliation: From the Human and Molecular Genetics Center (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., C.C.H., H.J.J., M.J.F., J.L.) and Departments of Physiology (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., H.J.J., M.J.F., J.L.), Pediatrics (H.J.J.), and Dermatology (J.L.), Medical College of Wisconsin, Milwaukee.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Prokop
authors.affiliation: From the Human and Molecular Genetics Center (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., C.C.H., H.J.J., M.J.F., J.L.) and Departments of Physiology (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., H.J.J., M.J.F., J.L.), Pediatrics (H.J.J.), and Dermatology (J.L.), Medical College of Wisconsin, Milwaukee.
authors.forename: Allison B
authors.initials: AB
authors.lastname: Sarkis
authors.affiliation: From the Human and Molecular Genetics Center (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., C.C.H., H.J.J., M.J.F., J.L.) and Departments of Physiology (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., H.J.J., M.J.F., J.L.), Pediatrics (H.J.J.), and Dermatology (J.L.), Medical College of Wisconsin, Milwaukee.
authors.forename: Nan Cher
authors.initials: NC
authors.lastname: Yeo
authors.affiliation: From the Human and Molecular Genetics Center (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., C.C.H., H.J.J., M.J.F., J.L.) and Departments of Physiology (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., H.J.J., M.J.F., J.L.), Pediatrics (H.J.J.), and Dermatology (J.L.), Medical College of Wisconsin, Milwaukee.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hoffman
authors.affiliation: From the Human and Molecular Genetics Center (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., C.C.H., H.J.J., M.J.F., J.L.) and Departments of Physiology (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., H.J.J., M.J.F., J.L.), Pediatrics (H.J.J.), and Dermatology (J.L.), Medical College of Wisconsin, Milwaukee.
authors.forename: Colin C
authors.initials: CC
authors.lastname: Hansen
authors.affiliation: From the Human and Molecular Genetics Center (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., C.C.H., H.J.J., M.J.F., J.L.) and Departments of Physiology (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., H.J.J., M.J.F., J.L.), Pediatrics (H.J.J.), and Dermatology (J.L.), Medical College of Wisconsin, Milwaukee.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.affiliation: From the Human and Molecular Genetics Center (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., C.C.H., H.J.J., M.J.F., J.L.) and Departments of Physiology (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., H.J.J., M.J.F., J.L.), Pediatrics (H.J.J.), and Dermatology (J.L.), Medical College of Wisconsin, Milwaukee.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Flister
authors.affiliation: From the Human and Molecular Genetics Center (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., C.C.H., H.J.J., M.J.F., J.L.) and Departments of Physiology (S.Z.P., J.W.P., A.B.S., N.C.Y., M.J.H., H.J.J., M.J.F., J.L.), Pediatrics (H.J.J.), and Dermatology (J.L.), Medical College of Wisconsin, Milwaukee. jlazar@mcw.edu.
authors.forename: Jozef
authors.initials: J
authors.lastname: Lazar
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D002874:Chromosome Mapping / Q000379:methods*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D007672:Kidney Cortex / Q000378:metabolism; D007679:Kidney Medulla / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D020303:Rats, Inbred Dahl; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000633:toxicity; D026801:Synteny
chemical_list: D017673:Sodium Chloride, Dietary
keywords: hypertension; rats, inbred BN; rats, inbred Dahl