Identification of hypertension-related genes through an integrated genomic-transcriptomic approach.
In search for the genetic basis of hypertension, we applied an integrated genomic-transcriptomic approach to identify genes involved in the pathogenesis of hypertension in the Sabra rat model of salt-susceptibility. In the genomic arm of the project, we previously detected in male rats two salt-susceptibility QTLs on chromosome 1, SS1a (D1Mgh2-D1Mit11; span 43.1 cM) and SS1b (D1Mit11-D1Mit4; span 18 cM). In the transcriptomic arm, we studied differential gene expression in kidneys of SBH/y and SBN/y rats that had been fed regular diet or salt-loaded. We used the Affymetrix Rat Genome RAE230 GeneChip and probed >30,000 transcripts. The research algorithm called for an initial genome-wide screen for differentially expressed transcripts between the study groups. This step was followed by cluster analysis based on 2x2 ANOVA to identify transcripts that were of relevance specifically to salt-sensitivity and hypertension and to salt-resistance. The two arms of the project were integrated by identifying those differentially expressed transcripts that showed an allele-specific hypertensive effect on salt-loading and that mapped within the defined boundaries of the salt-susceptibility QTLs on chromosome 1. The differentially expressed transcripts were confirmed by RT-PCR. Of the 2933 genes annotated to rat chromosome 1, 1102 genes were identified within the boundaries of the two blood pressure QTLs. The microarray identified 2470 transcripts that were differentially expressed between the study groups. Cluster analysis identified genome-wide 192 genes that were relevant to salt-susceptibility and/or hypertension, 19 of which mapped to chromosome 1. Eight of these genes mapped within the boundaries of QTLs SS1a and SS1b. RT-PCR confirmed 7 genes, leaving TcTex1, Myadm, Lisch7, Axl-like, Fah, PRC1-like, and Serpinh1. None of these genes has been implicated in hypertension before. These genes become henceforth targets for our continuing search for the genetic basis of hypertension.
Yagil
Chana
C
Israel Rat Genome Center and Laboratory for Molecular Medicine, Department of Nephrology and Hypertension, Faculty of Health Sciences, Barzilai Medical Center Campus of the Ben-Gurion University, Ashkelon, Israel.
Hubner
Norbert
N
Monti
Jan
J
Schulz
Herbert
H
Sapojnikov
Marina
M
Luft
Friedrich C
FC
Ganten
Detlev
D
Yagil
Yoram
Y
D000465:Algorithms; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D002874:Chromosome Mapping; D003900:Desoxycorticosterone / Q000008:administration & dosage / Q000633:toxicity; D004343:Drug Implants; D004398:Dyneins; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D023281:Genomics; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics; D006867:Hydrolases / Q000235:genetics; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics*; D007668:Kidney / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011919:Rats, Inbred Strains; D011973:Receptors, LDL / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D056427:t-Complex Genome Region
D000943:Antigens, Differentiation; D004343:Drug Implants; C533388:Dynlt1 protein, rat; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C503871:Lsr protein, rat; D008869:Microtubule-Associated Proteins; C503869:Myadm protein, rat; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011973:Receptors, LDL; C494662:Serpinh1 protein, rat; D015843:Serpins; D017673:Sodium Chloride, Dietary; D014157:Transcription Factors; D003900:Desoxycorticosterone; D006867:Hydrolases; D004398:Dyneins; C020156:fumarylacetoacetase