Isolation of a chromosome 1 region affecting blood pressure and vascular disease traits in the stroke-prone rat model.
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 F1(SHRSP/IzmxWKY/Izm)xSHRSP/Izm back-cross (n=63) 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 F1 back-cross studied. Second, we also investigated linkage to BP in F2 progeny (n=175) involving the stroke-resistant (or normal) spontaneously hypertensive rat (SHR). In F2 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.
Kato
Norihiro
N
Department of Gene Diagnostics and Therapeutics, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. nokato@ri.imcj.go.jp
Nabika
Toru
T
Liang
Yi-Qiang
YQ
Mashimo
Tomoji
T
Inomata
Hyoe
H
Watanabe
Takehiro
T
Yanai
Kazuyuki
K
Yamori
Yukio
Y
Yazaki
Yoshio
Y
Sasazuki
Takehiko
T
D000818:Animals; D020296:Animals, Congenic; D001794:Blood Pressure / Q000235:genetics*; D033481:Chromosomes, Mammalian; D005260:Female; D015870:Gene Expression; D008040:Genetic Linkage; D005819:Genetic Markers; D006973:Hypertension / Q000150:complications* / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats; D010641:Phenotype; D040641:Quantitative Trait Loci; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020521:Stroke / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D014652:Vascular Diseases / Q000235:genetics
D005819:Genetic Markers