Genetic Isolation of a Chromosome 1 Region Affecting Blood Pressure in the Spontaneously Hypertensive Rat

Lezin, Elizabeth St.; Liu, Weizhong; Wang, Jiaming; Wang, Ning; Křen, Vladimı́r; Křenová, D; Musilová, Alena; Zdobinská, M; Zidek, Vaclav; Lau, Daniel; Pravenec, Michal

doi:10.1161/01.hyp.30.4.854

Cited by 46 publications

(41 citation statements)

References 29 publications

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“…In rat, it is located in a region of chromosome 1q34 harboring quantitative trait loci (QTL) for blood pressure, type 2 diabetes (T2D) mellitus, body weight, cardiac mass, and kidney mass. Compelling evidence supports the existence of several genes accounting for these blood pressure QTL in hypertensive rat strains (20)(21)(22)(23)(24). Recent work in a congenic strain (Sisa1a) designed to dissect one of these QTL has identified a 3-Mb region in SHR with significant impact on blood pressure (25).…”

mentioning

confidence: 94%

Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes

Woon

Kaisaki

Bragança

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

350

239

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Many aspects of physiology and behavior follow a circadian rhythm. Brain and muscle Arnt-like protein-1 (BMAL1) is a key component of the mammalian molecular clock, which controls circadian oscillations. In the rat, the gene encoding Bmal1 is located within hypertension susceptibility loci. We analyzed the SNP distribution pattern in a congenic interval associated with hypertension in the spontaneously hypertensive rat (SHR), and we show that Bmal1 maps close to a region genetically divergent between SHR and its normotensive (Wistar-Kyoto) counterpart. Bmal1 sequencing in rat strains identified 19 polymorphisms, including an SHR promoter variant that significantly affects Gata-4 activation of transcription in transient transfection experiments. A genetic association study designed to test the relevance of these findings in 1,304 individuals from 424 families primarily selected for type 2 diabetes showed that two BMAL1 haplotypes are associated with type 2 diabetes and hypertension. This comparative genetics finding translated from mouse and rat models to human provides evidence of a causative role of Bmal1 variants in pathological components of the metabolic syndrome.comparative genomics ͉ genetic polymorphism ͉ molecular clock ͉ SNP ͉ sequence variation

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mentioning

confidence: 94%

Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes

Woon

Kaisaki

Bragança

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

350

239

View full text Add to dashboard Cite

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“…However, the mean blood pressure effect measured in these congenic rat strains was relatively small clearly indicating that the transferred regions do not contain major genes for hypertension of the spontaneously hypertensive SHR/SHRSP rats (2)(3)(4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 94%

“…Regarding the locus order on the chromosomes, recombination events were found proximally or distally in the majority of chromosomes, but there were also double recombination events on chromosomes 2, 3 and 7. The selected male of the BC2 generation with a mean blood pressure of 160 mmHg was already homozygous at all loci on 6 chromosomes (3,8,10,11,13,15) suggesting that one heterozygous haploid chromosome was most probably completely substituted by that of the BB/OK rat backcrossed. Heterozygosity was found at all loci studied on chromosomes 14 and 16 whereas some of the loci on 9 chromosomes were heterozygous as found in the BC1 male (1, 2, 5, 11, 10, 12, 17, 18, 19).…”

Section: Introductionmentioning

confidence: 99%

Phenotypic selection: A successful strategy to fix major genes of hypertension

1999

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SUMMARYHypertension is dominantly inherited in cross hybrids between hypertensive SHR/Mol and normotensive BB/OK rats. We used these cross hybrids for repeated backcrossing of selected hypertensive animals onto normotensive BB/OK rats to fix high blood pressure and to generate a hypertensive and diabetic BB/OK rat subline. After 8 backcrosses, the backcross parents were genetically analysed with the aid of 259 microsatellite markers to identify SHR genes causing blood pressure of 177 + 10 mmHg in this BB/OK rat subline. Loci on chromosomes 1, 14 and 18 showed longest heterozygosity. These loci might contain major genes of the SHR rat causing hypertension in this BB/OK rat subline. This classical strategy seems to be most suitable to fix major genes of hypertension in particular and complex traits in general and therefore to generate new animal models.

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“…22 In an elegant series of experiments, they compared the BP effects of a 4-way transplantation protocol: SHR kidney into SHR recipient (SHR shr ), CSHR kidney into SHR recipient (SHR cshr ), SHR kidney into CSHR recipient (CSHR shr ), and CSHR kidney into CSHR recipient (CSHR cshr ). The transplants were carried out at 6 to 8 weeks of age, and BP development was monitored by continuous radiotelemetry for 8 weeks.…”

Section: Clemitson Et Al Tissue Specificity Of Chromosome 1 Bp Qtl 295mentioning

confidence: 99%

Kidney Specificity of Rat Chromosome 1 Blood Pressure Quantitative Trait Locus Region

et al. 2002

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Abstract-Rat chromosome 1 has a region containing loci that influence blood pressure. In the present study, we investigated whether these loci mediate their effect via the kidney. Taking advantage of the histocompatability between a congenic strain (WKY.SHR-Sa, which contains the relevant chromosomal region from the spontaneously hypertensive rat) and its parental strain, the Wistar-Kyoto rat (WKY), we compared the effect of transplanting a kidney at 5 to 6 weeks of age from either congenic rats or WKY into bilaterally nephrectomized WKY. WKY.SHR-Sa animals and WKY with intact kidneys and with unilateral nephrectomy were studied as controls. Blood pressure was measured at 12, 16, 20, and 25 weeks of age. At all time points, blood pressure was significantly higher (by between 8 to 22 mm Hg, PϽ0.001) in 2-kidney WKY.SHR-Sa animals compared with WKY. This genotype-related difference was maintained in unilaterally nephrectomized rats. Most importantly, WKY that received transplants from WKY.SHR-Sa rats had significantly higher blood pressure (PϽ0.001 at all time points) compared with those that received transplants from other WKY. At any age, this difference was between 70% to 100% of the difference observed between the 1-kidney groups. There was no difference in plasma urea or creatinine between groups or evidence of chronic rejection in the cross-transplant group.The findings indicate that the major proportion of the blood pressure effect of loci on rat chromosome 1 is mediated through the kidney, and provide a rational basis for investigating genes located in the relevant chromosomal region and expressed in the kidney as likely candidates. Key Words: hypertension, experimental Ⅲ genetics Ⅲ rats, spontaneously hypertensive Ⅲ genes Ⅲ transplantation, renal I n the past decade, quantitative trait loci (QTLs) affecting blood pressure (BP) have been mapped to regions on several rat chromosomes by use of linkage analysis in segregating progeny from crosses of inbred hypertensive and normotensive rat strains. 1 In many instances, the presence of the QTLs has been confirmed by their capture in congenic strains. 1 These are strains in which a chromosomal region from one strain (eg, a hypertensive strain) is introgressed into another (eg, normotensive) strain by marker-selected backcrossing. 2 If the QTL is present in the introgressed segment, the congenic strain should have a different BP (higher in the above example) than that of the recipient parental strain.In previous studies, we 3 and others 1 have shown that a region in the midportion of rat chromosome 1 (RNO1) has Ն1 QTLs affecting BP. In second filial generation (F 2 ) progeny from a cross of the spontaneously hypertensive rat (SHR) and the Wistar-Kyoto rat (WKY) strains, the QTL region accounted for Ϸ25% of the variance in BP. 3 This segment of RNO1 is particularly interesting because it also harbors QTLs for stroke latency, 4 renal damage, 5 and diabetes-related phenotypes. 6 More recently, we have captured the region containing the BP QTL(s) in reciprocal conge...

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Genetic Isolation of a Chromosome 1 Region Affecting Blood Pressure in the Spontaneously Hypertensive Rat

Cited by 46 publications

References 29 publications

Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes

Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes

Phenotypic selection: A successful strategy to fix major genes of hypertension

Kidney Specificity of Rat Chromosome 1 Blood Pressure Quantitative Trait Locus Region

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