Systematic polymorphism discovery after genome-wide identification of potential susceptibility loci in a hereditary rodent model of human hypertension

Abstract

Genetic strategies such as linkage analysis and quantitative trait locus (QTL) mapping have identified a multitude of loci implicated in the pathogenesis of hypertension in the spontaneously hypertensive rat (SHR). While several candidate genetic regions have been identified in the SHR and its control, the Wistar–Kyoto rat (WKY), systematic follow-up of candidate identification with polymorphism discovery has not been widespread. In the current report, we develop a data-mining strategy to identify candidate genes for hypertension in the SHR, and then sequence each gene in the SHR and WKY strains. We integrate blood pressure QTL data, microarray data and data-mining methods. First, we determined the set of genes differentially expressed in SHR and WKY adrenal glands. Next, the chromosomal position of all differentially expressed genes was compared with peak marker position of all reported SHR blood pressure QTLs. We also identified the set of differentially expressed genes with the most extreme fold-change. Finally, the QTL positional candidates and the genes with extreme differential expression were proposed as candidate genes if they had biologically plausible roles in hypertensive pathology. We identified seven candidate genes that merit resequencing (catechol-O-methyltransferase [Comt], chromogranin A [Chga], dopamine beta-hydroxylase [Dbh], electron transferring flavoprotein dehydrogenase [Etfdh], endothelin receptor type B [Ednrb], neuropeptide Y [Npy] and phenylethanolamine-N-methyltransferase [Pnmt]), and then discovered polymorphism in four of these seven candidate genes. Chga is proposed as the strongest candidate for additional functional investigation. Our method for candidate gene identification is portable and can be applied to microarray data from any tissue, in any disease model with a QTL database.

Medicinal Chemistry of CatecholO-Methyltransferase (COMT) Inhibitors and Their Therapeutic Utility

“…However, there is evidence in the literature that conflicts with these views 72 , namely, with respect to experimental models of hypertension. 73 The inhibition of peripheral COMT, which prevents the mucosal degradation of dopamine, along with various dopamine receptor agonists ameliorates gastroduodenal mucosal damage.…”

Daily dynamic of indicators of girl-students’ blood micro-circulation

“…Such scientists like Friese R.S., Edwards K.M. [19] research blood micro-circulation with hyper-tension. Mills P.J., Heller M.J., [3,6,7,8].…”

“…It is evident that changes in blood microcirculation's system are in close correlation with shifts in central haemo-dynamic. It permits to use parameters of micro-circulation as criteria in assessment of examined persons' health 11,17,19].…”

Features of reactivity of students` capillary blood flow

“…Такі вчені як, Friese R. S., Edwards K. M. [3,4] проводять дослідження мікроциркуляції крові при гіпертензії. Mills P. J., Heller M. J., Lefkowitz R. B., Schmid-Schönbein G. W. [4,5] вивчають ферментні фракції крові.…”