Published online before print July 20, 2009, doi: 10.1161/HYPERTENSIONAHA.108.126664
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(Hypertension. 2009;54:639.)
© 2009 American Heart Association, Inc.
Original Articles |
Dissection of Chromosome 18 Blood Pressure and Salt-Sensitivity Quantitative Trait Loci in the Spontaneously Hypertensive Rat
From the Physiological Genomics and Medicine Group (M.D.J., L.H., C.A.W., T.J.A.), Medical Research Council Clinical Sciences Centre, Imperial College London, London, United Kingdom; Department of Genetics (D.H., H.W., C.E.S., J.G.S.), Harvard Medical School, Boston, Mass; Institute of Physiology (V.Z., P.M., A.M., M.S., J.V., V.K., M.P.), Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology and Medical Genetics (V.K., M.P.), 1st Medical Faculty, Charles University, Prague, Czech Republic; Institute for Clinical and Experimental Medicine (O.V.), Prague, Czech Republic; Department of Medicine (N.R.Q.), University of Michigan Medical School, Ann Arbor, Mich; Department of Laboratory Medicine (J.W., T.W.K.), University of California, San Francisco, Ca; Howard Hughes Medical Institute (C.E.S.), Boston, Mass.
Correspondence to Michal Pravenec, Institute of Physiology, Czech Academy of Sciences, Víde
ská 1083, 142 20 Prague 4, Czech Republic. E-mail pravenec{at}biomed.cas.cz; and Timothy J. Aitman, MRC Clinical Sciences Centre, Du Cane Rd, London W12 0NN, UK. E-mail: t.aitman@csc.mrc.ac.uk.
Hypertension in humans and experimental models has a strong hereditary basis, but identification of causative genes remains challenging. Quantitative trait loci (QTLs) for hypertension and salt sensitivity have been reported on rat chromosome 18. We set out to genetically isolate and prioritize genes within the salt-sensitivity and hypertension QTLs on the spontaneously hypertensive rat (SHR) chromosome 18 by developing and characterizing a series of congenic strains derived from the SHR and normotensive Brown Norway rat strains. The SHR.BN-D18Rat113/D18Rat82 congenic strain exhibits significantly lower blood pressure and is salt resistant compared with the SHR. Transplantation of kidneys from SHR.BN-D18Rat113/D18Rat82 donors into SHR recipients is sufficient to attenuate increased blood pressure but not salt sensitivity. Derivation of congenic sublines allowed for the separation of salt sensitivity from hypertension QTL regions. Renal expression studies with microarray and Solexa-based sequencing in parental and congenic strains identified 4 differentially expressed genes within the hypertension QTL region, one of which is an unannotated transcript encoding a previously undescribed, small, nonprotein coding RNA. Sequencing selected biological candidate genes within the minimal congenic interval revealed a nonsynonymous variant in SHR transcription factor 4. The minimal congenic interval is syntenic to a region of human chromosome 18 where significant linkage to hypertension was observed in family based linkage studies. These congenic lines provide reagents for identifying causative genes that underlie the chromosome 18 SHR QTLs for hypertension and salt sensitivity. Candidate genes identified in these studies merit further investigation as potentially causative hypertension genes in SHR and human hypertension.
Key Words: hypertension • salt sensitivity • congenic • microarray expression profiling • candidate genes
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