Isolation of a Chromosome 1 Region Affecting Blood Pressure and Vascular Disease Traits in the Stroke-Prone Rat Model

Abstract

Abstract-Recently, a genome-wide screen has shown a major quantitative trait locus (QTL) for a stroke-associated phenotype on rat chromosome 1 (RNO1) independent of QTL for blood pressure (BP) in the stroke-prone spontaneously hypertensive rat (SHRSP) of a Heidelberg colony. However, it remains to be elucidated whether these observations reflect the existence of different genes predisposing to each of the disorders. To address this issue, we performed comprehensive approaches in a Japanese colony, Izm, as follows. First, we undertook genome-wide searches in F 1 (SHRSP/IzmϫWKY/Izm)ϫSHRSP/Izm back-cross (nϭ63) to pursue a causal relation between hypertension and stroke. Although the strongest linkage to BP (LOD score of 3.4) was identified on RNO1, its relevance to stroke was not supported in the F 1 back-cross studied. Second, we also investigated linkage to BP in F 2 progeny (nϭ175) involving the stroke-resistant (or normal) spontaneously hypertensive rat (SHR). In F 2 studies of SHR/Izm, this locus did not appear to constitute a principal BP QTL. Third, we constructed congenic animals with detailed phenotype characterization. Transfer of a chromosomal fragment between markers Klk1 and D1Rat116 from WKY/Izm onto the SHRSP/Izm background lowered systolic BP by 20 to 80 mm Hg, prevented development of apparent stroke, and exaggerated impaired glucose tolerance. In conclusion, we have successfully isolated an RNO1 region affecting BP, stroke, and glucose tolerance in SHRSP/Izm-derived congenic rats. The size of the introgressed region is large, but our novel congenic strain should help delineate complex, genetic impairments underlying BP and associated vascular disease phenotypes.

Sympathetic Regulation of the Renal Functions in Rats Reciprocally Congenic for Chromosome 1 Blood Pressure Quantitative Trait Locus

“…Our study clearly illustrated a major effect of the chr-1 QTL on this phenotype, which was independent of the genetic background. This contrasted well with the case of BP per se; in the adult congenic strains, BP was only marginally different between WKYpch1.0 and WKY (7,22), but was significantly lower in SHRSPwch1.0 compared to SHRSP (11,12). This means that BP is a more "remote" phenotype under more complex control by a number of genetic and environmental factors.…”

The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

“…[25][26][27] Simultaneously, our search of intermediate phenotypes indicated sympathetic hyper-responsiveness to stresses in the congenic strains constructed for this QTL. [28][29][30] A follow-up study using preparations of isolated neonatal brain stem confirmed that the electrophysiological nature of neurons in the rostral ventrolateral medulla, one of the most important centers for sympathetic activity regulation, were influenced by the Chr 1 QTL, suggesting that rostral ventrolateral medulla is one of the primary targets of the gene(s) in this QTL.…”

Mapping genetic determinants of kidney damage in rat models

“…On RNO1 several QTLs linked to BP, 47,48,54,77,90,[177][178][179][180][181][182][183] stroke or strokeassociated phenotypes, 182,184 and renal damages 48,54,77,90,141,142,151 could be identified in different rat models. To demonstrate genetic differences in the incidence of hypertension, cerebral stroke and renal damage under salt loading in tap water (1% NaCl), Ishikawa et al 185 analysed five congenic rat strains, in which different chromosomal segments from WKY/Izm-RNO1 were transferred into the SHRSP/ Izm background ( Table 2).…”