Published online before print February 24, 2005, doi: 10.1161/01.RES.0000160556.52369.61
© 2005 American Heart Association, Inc.
Molecular Medicine |
Identification of Hypertension-Related Genes Through an Integrated Genomic-Transcriptomic Approach
From the Israel Rat Genome Center and Laboratory for Molecular Medicine (C.Y., M.S., Y.Y.), Department of Nephrology and Hypertension, Faculty of Health Sciences, Barzilai Medical Center Campus of the Ben-Gurion University, Ashkelon, Israel; Max-Delbruck-Center for Molecular Medicine (MDC) (N.H., J.M., H.S., F.C.L., D.G.), Berlin-Buch; and Medical Faculty of the Charite (J.M., F.C.L.), Franz Volhard Clinic, HELIOS Klinikum, Berlin, Germany.
Correspondence to Yoram Yagil, MD, FAHA, Israel Rat Genome Center and Laboratory for Molecular Medicine, Department of Nephrology and Hypertension, Barzilai Medical Center Campus, Ashkelon 78306, Israel. E-mail labmomed{at}bgumail.bgu.ac.il
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.
Key Words: linkage • DNA microarrays • transcripts • candidate genes • salt-susceptibility
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