Dissection of chromosome 18 blood pressure and salt-sensitivity quantitative trait loci in the spontaneously hypertensive rat.
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.
Johnson
Michelle D
MD
Institute of Physiology, Czech Academy of Sciences, Vídenská 1083, 142 20 Prague 4, Czech Republic.
He
Liqun
L
Herman
Daniel
D
Wakimoto
Hiroko
H
Wallace
Caroline A
CA
Zidek
Vaclav
V
Mlejnek
Petr
P
Musilova
Alena
A
Simakova
Miroslava
M
Vorlicek
Jaroslav
J
Kren
Vladimir
V
Viklicky
Ondrej
O
Qi
Nathan R
NR
Wang
Jiaming
J
Seidman
Christine E
CE
Seidman
Jonathan
J
Kurtz
Theodore W
TW
Aitman
Timothy J
TJ
Pravenec
Michal
M
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics* / Q000502:physiology; D015152:Blotting, Northern; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006973:Hypertension / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D007668:Kidney / Q000378:metabolism; D016030:Kidney Transplantation / Q000379:methods; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D051381:Rats; D011914:Rats, Inbred BN; D011918:Rats, Inbred SHR; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics; D044101:Receptors, Melanocortin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017673:Sodium Chloride, Dietary / Q000009:adverse effects
D051017:Apoptosis Regulatory Proteins; C542951:CIDEA protein, rat; D044103:Receptor, Melanocortin, Type 2; D044105:Receptor, Melanocortin, Type 4; D044101:Receptors, Melanocortin; D017673:Sodium Chloride, Dietary; C086971:melanocortin 5 receptor; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; C516654:Ptpn2 protein, rat