title: Two genomic regions of chromosomes 1 and 18 explain most of the stroke susceptibility under salt loading in stroke-prone spontaneously hypertensive rat/Izm.
abstract: To clarify the genetic mechanisms of stroke susceptibility in the stroke-prone spontaneously hypertensive rat (SHRSP), a quantitative trait locus (QTL) analysis was performed. Using 295 F2 rats of a cross between SHRSP/Izm and SHR/Izm, 2 major QTLs for stroke latency under salt loading were identified on chromosomes (chr) 1 and 18. Evaluation of 6 reciprocal single and double congenic rats for these QTLs showed that substitution of the SHRSP for the SHR fragment at the chr 1 and 18 QTLs increased the relative risk for stroke by 8.4 and 5.0, respectively. The combined effect of the 2 QTLs was 10× greater than that of the background genome (by Cox hazard model). Blood pressure monitoring by radio telemetry indicated that the combination of the 2 QTLs had a clear effect on the salt-dependent blood pressure increase, suggesting an important role for the salt-sensitive blood pressure increase in the susceptibility of SHRSP to stroke. A haplotype analysis of 11 substrains of SHRSP and SHR using 340 simple sequence repeat markers in the chr 1 QTL suggested that the 7-Mbp fragment between D1Rat260 and D1Rat178 was most likely to harbor the responsible gene(s), which was confirmed by a study of additional subcongenic strains. This study indicated a major role for 2 QTLs on chr 1 and 18 in stroke susceptibility in SHRSP under salt loading. The salt-sensitive blood pressure increase was implied to play a key role in the stroke susceptibility.
authors.affiliation: Department of Functional Pathology, Shimane University Faculty of Medicine, Izumo, Japan.
authors.forename: Tsend-Ayush
authors.initials: TA
authors.lastname: Gandolgor
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ohara
authors.forename: Zong-Hu
authors.initials: ZH
authors.lastname: Cui
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Hirashima
authors.forename: Toshiko
authors.initials: T
authors.lastname: Ogawa
authors.forename: Kathrin
authors.initials: K
authors.lastname: Saar
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Minoru
authors.initials: M
authors.lastname: Isomura
authors.forename: Toru
authors.initials: T
authors.lastname: Nabika
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006973:Hypertension / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D018895:Microsatellite Repeats; D040641:Quantitative Trait Loci; D051381:Rats; D011918:Rats, Inbred SHR; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D020521:Stroke / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology
chemical_list: D017673:Sodium Chloride, Dietary; D004247:DNA
keywords: genetics; quantitative trait loci; rats, inbred SHR; salt; stroke