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(Hypertension. 2005;45:451.)
© 2005 American Heart Association, Inc.

Original Articles

Locating a Blood Pressure Quantitative Trait Locus Within 117 kb on the Rat Genome

Substitution Mapping and Renal Expression Analysis

Michael R. Garrett; Haijin Meng; John P. Rapp; Bina Joe

From the Department of Physiology and Cardiovascular Genomics, Medical College of Ohio, Toledo. Haijin Meng’s present address is Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA 90095.

Correspondence to Bina Joe, PhD, Department of Physiology and Cardiovascular Genomics, Medical College of Ohio, 3035 Arlington Ave, Toledo, OH 43614-5804. E-mail bjoe{at}mco.edu

Abstract

Previously, a blood pressure (BP) quantitative trait locus (QTL) on rat chromosome 9 (RNO9) was localized to a <2.4 cM interval using congenic strains generated by introgressing segments of RNO9 from the Dahl salt-resistant (R) rat into the background of the Dahl salt-sensitive (S) rat. Renal gene expression using Affymetrix gene chips was profiled on S and a congenic strain spanning the 2.4-cM BP QTL interval. This analysis identified 20 differentially expressed genes/expressed sequence tags. Of these, the locus with the greatest differential expression (30- to 35-fold) was regulated endocrine-specific protein 18 (Resp18), which also mapped in the 2.4-cM BP QTL interval. Additional substitution mapping located the QTL to <0.4 cM or 493 kb. This newly defined QTL region still included Resp18. Nucleotide variants were identified between S and R genomic DNA of Resp18 in the coding, 5' regulatory and 3' untranslated regions. The coding sequence variation (T/C) occurs in exon 2 and predicts an amino acid change (Ile/Val) in the protein product. Resp18 was considered a differentially expressed positional candidate for the QTL. To fine-map the BP QTL, we constructed a congenic strain with a smaller introgressed region. Compared with the S rat, this strain (1) had significantly lower BP, (2) did not contain the R form of Resp18, and (3) did not retain the rather spectacular differential expression of Resp18. Together, these results demonstrate that a BP QTL independent of Resp18 exists within the newly defined 117-kb QTL region on RNO9.

Key Words: hypertension, genetic • genes • cardiovascular diseases

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