Combined genealogical, mapping, and expression approaches to identify spontaneously hypertensive rat hypertension candidate genes.

TitleCombined genealogical, mapping, and expression approaches to identify spontaneously hypertensive rat hypertension candidate genes.
Publication TypeJournal Article
Year of Publication2005
AuthorsHinojos, CA, Boerwinkle, E, Fornage, M, Doris, PA
Date Published2005 Apr
KeywordsAnimals, Blood Pressure, Chromosome Mapping, Expressed Sequence Tags, Gene Expression, Genome, Hypertension, Kidney, Oligonucleotide Array Sequence Analysis, Pedigree, Quantitative Trait Loci, Rats, Rats, Inbred SHR, Rats, Inbred WKY, Regression Analysis, Species Specificity

Allelic expression in genes has become recognized as a heritable trait by which phenotypes are generated. We have examined gene expression in the rat kidney using genome-wide microarray technology (Affymetrix). Gene expression was determined across 4 rat strains, 3 hypertensive spontaneously hypertensive rat (SHR) substrains (SHR-A3, SHR-B2, and SHR-C), and a normotensive strain (Wistar-Kyoto [WKY]). Expression measurements were made in multiple animals from all strains at 4 time points (4 weeks, 8 weeks, 12 weeks, and 18 weeks of age), covering the prehypertensive period in SHR (4 weeks), and the period of rapidly rising blood pressure (8 and 12 weeks) and of sustained hypertension (18 weeks). Regression analysis revealed a close relationship across all strains during the first 3 time points, after which SHR-A3 became a substantial outlier. SHR-B2 and SHR-C demonstrated a very close relationship in gene expression at all times but also showed increased differences compared with the other strains at 18 weeks of age. We identified genes that were consistently different in expression, comparing all SHR substrains at each time point with WKY. The resulting list of genes was compared with blood pressure quantitative trait loci reported for SHR to refine a number of genes consistently differentially expressed between SHR substrains and WKY, persistently differentially expressed across multiple time points, and located in SHR blood pressure-determinative regions of the genome. Genealogical relationships and SHR substrain intercrosses suggest that genes responsible for heritable hypertension in SHR are shared across SHR substrains. The present approach identifies a number of genes that may influence blood pressure in SHR by virtue of allelic effects on gene expression.

Alternate JournalHypertension
PubMed ID15710778
Grant ListDDK45538 / DK / NIDDK NIH HHS / United States
HL51021 / HL / NHLBI NIH HHS / United States
HL69126 / HL / NHLBI NIH HHS / United States
NS41466 / NS / NINDS NIH HHS / United States

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