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From the Departments of Cardiology (S.A.F., M.K., N.J.S.) and
Ophthalmology (J.R.T.), University of Leicester, Leicester, UK; the School of
Biological Sciences, University of Nottingham, UK (S.M.G., T.B.); Wellcome
Trust Center for Human Genetics, University of Oxford, Oxford, UK (D.G.); and
URA Centre National de la Recherche Scientifique 1483, Faculte de Pharmacie,
Lyon, France (M.V.). Dr Vincent is currently at the Laboratoire de
Physiologie, Faculte de Medecine, Lyon, France.
Abstract—Linkage
analyses in experimental crosses of hypertensive and
normotensive rats have strongly suggested the presence of a
quantitative trait locus (QTL) influencing blood pressure on rat
chromosome 1, at or near the Sa gene. To confirm the
presence of such a locus and move toward identification of the
causative gene, we have developed, through targeted breeding over 10
generations using an Sa gene polymorphism to select
breeders at each generation, 2 congenic strains, 1 containing a segment
of spontaneously hypertensive rat (SHR) chromosome 1 in a Wistar-Kyoto
rat (WKY) genetic background (WKY.SHR-Sa), and the other
a segment of WKY chromosome 1 in an SHR background
(SHR.WKY-Sa). WKY.SHR-Sa contains at
least
© 1998 American Heart Association, Inc.
Scientific Contributions
Successful Isolation of a Rat Chromosome 1 Blood Pressure Quantitative Trait Locus in Reciprocal Congenic Strains
26 cM of SHR chromosome 1, between markers
mD7mit206 and D1Mit2 (and including the
SHR allele of the Sa gene), and
SHR.WKY-Sa carries at least 15 cM of WKY chromosome
1, between mD7mit206 and D1Wox34 (and
including the WKY allele of the Sa gene). Blood
pressure of WKY.SHR-Sa rats measured at 16, 20, and 25
weeks of age was significantly higher than that of WKY, whereas blood
pressure of SHR.WKY-Sa rats was significantly lower than
that of SHR. At 25 weeks, the mean differences in systolic and
diastolic blood pressure between WKY.SHR-Sa
and WKY were +11.5 mm Hg (P=0.001) and +11.6
mm Hg mm Hg (P<0.001), respectively. The
corresponding differences between SHR.WKy-Sa and SHR
were -11.3 mm Hg (P=0.002) and -9.1 mm Hg
(P=0.005), respectively. The differences
represent about one fifth of the blood pressure difference
between SHR and WKY. Renal Sa mRNA levels in the
congenic strains reflected their Sa allele with a
high level in WKY.SHR-Sa and a low level in
SHR.WKY-Sa, consistent with previous data
suggesting that the level of Sa expression is primarily
determined by cis-acting elements in or near the
Sa gene. Our results show that we have successfully
isolated a major rat chromosome 1 blood pressure QTL located in the
vicinity of the Sa gene in reciprocal congenic strains
derived from SHR and WKY. The strains can now be used to further define
the region containing the QTL and also to characterize intermediary
mechanisms through which the QTL influences blood pressure. In
addition, comparison of the regions introgressed in our congenic
strains with the location of the peak LOD score for chromosome 1 blood
pressure QTL in second filial generation progeny derived from our
SHRxWKY cross suggests that there may be at least 1 further QTL
influencing blood pressure on this rat chromosome.
Key Words: hypertension, genetic • congenic strains • quantitative trait locus • genes • rats, inbred SHR
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