Successful Isolation of a Rat Chromosome 1 Blood Pressure Quantitative Trait Locus in Reciprocal Congenic Strains

Frantz, Simon; Kaiser, Michael; Gardiner, Sheila M.; Guyader, Dominique; Vincent, Madeleine; Thompson, John R.; Bennett, T.; Samani, Nilesh J.

doi:10.1161/01.hyp.32.4.639

Cited by 45 publications

(72 citation statements)

References 54 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).…”

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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.

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350

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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.

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350

239

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“…The congenic mice can then be studied to determine the effect of genetic background on the disease phenotype, and to map and identify disease-modifying genes. This approach has already been used to study the effect of varying genetic background on obesity, 1,2 diabetes, 3,4 transplant rejection, 5 hypertension, 6 and immunological responses. 7 Genetic studies of atherosclerosis, using mouse models, have mainly involved studies in which different inbred strains of mice are fed a high-fat, high-cholesterol, cholatecontaining diet developed in the laboratory of Paigen et al 8,9 By using this diet, inbred strains were characterized as susceptible, resistant, or intermediate, based on quantitative lesion area measurements.…”

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confidence: 99%

Genetic Background Determines the Extent of Atherosclerosis in ApoE-Deficient Mice

Dansky

Charlton

Sikes

et al. 1999

ATVB

151

135

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Abstract-Two strains of ApoE-deficient mice were found to have markedly different plasma lipoprotein profiles and susceptibility to atherosclerosis when fed either a low-fat chow or a high-fat Western-type diet. FVB/NJ ApoE-deficient (FVB E0) mice had higher total cholesterol, HDL cholesterol, ApoA1, and ApoA2 levels when compared with C57BL/6J ApoE-deficient (C57 E0) mice. At 16 weeks of age, mean aortic root atherosclerotic lesion area was 7-to 9-fold higher in chow diet-fed C57 E0 mice and 3.5-fold higher in Western diet-fed C57 E0 mice compared with FVB E0 mice fed similar diets. Lesion area in chow diet-fed first-generation mice from a strain intercross was intermediate in size compared with parental values. The distribution of the lesion area in 150 chow diet-fed second-generation progeny spanned the range of the lesion area in both parental strains. There were no correlations between total cholesterol, non-HDL cholesterol, HDL cholesterol, ApoA1, ApoA2, ApoJ, or anti-cardiolipin antibodies and lesion area in the second-generation progeny. Thus, a genomic approach may succeed in identifying the genes responsible for the variation in atherosclerosis susceptibility in these 2 strains of ApoE-deficient mice, which could not be explained by measured plasma parameters.

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“…This was actually suggested in the studies of congenic strains for the renin locus on chromosome 13 4,5,8 and for the Sa region on chromosome 1. 9 Considering the region shared by the four congenic strains reported so far for the Sa locus, a small fragment between D1Rat139 and D1Wox34 seems most likely to contain a hypertension gene (Fig. SHR, spontaneously hypertensive rats; WKY, Wistar-Kyoto rats; LEW, Lewis rats; BB, BioBreeding rats; DRY, Donryu rats; SHRSP, stroke-prone SHR; DS, Dahl salt-sensitive rats; FHH, Fawn hooded hypertensive rats; ACI, Augusta-Copenhagen-Irish rats; SBH, Sabra hypertensive rats; SBN, Sabra normotensive rats; BN, Brown Norway rats; RI, recombinant inbred strains; MNS, Milan normotensive strain; LH, Lyon hypertensive strain; LN, Lyon normotensive strain; DR, Dahl salt-resistant rats.…”

Section: The Entire Qtl Region Versus the Candidate Locusmentioning

confidence: 99%

“…Naturally, this observation cannot be applied directly to other congenics made from different sets of donor and recipient strains because QTL are potentially different among parental strains, even if cosegregation occurs in the same chromosomal regions. Rapp et al argued repeatedly that normotensive alleles introgressed into the DS genome had greater effects on blood pressure than did the hypertensive DS alleles transferred into the genomes of normotensive rats, suggesting significant effects of the genetic background 9 St Lezin et al 10 and Iwai et al 11 (b) A congenic strain constructed between stroke-prone spontaneously hypertensive rats/Izm and Wistar-Kyoto rats/Izm. A log of odds (LOD) plot is shown with the area introgressed into a congenic strain.…”

Section: Figmentioning

confidence: 99%

“…[12][13][14] However, not much experimental data are available with which to evaluate this hypothesis; only two sets of reciprocal congenics have been studied to date. 4,5,9 One of them was made for the Sa locus using SHR and WKY rats. Because the magnitude of blood pressure changes was comparable between the reciprocal congenics for the Sa locus, background effects on this locus were not likely.…”

Section: Normotensive Background Versus Hypertensive Backgroundmentioning

confidence: 99%

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Congenic Rats For Hypertension: How Useful Are They For The Hunting Of Hypertension Genes?

Nabika

Kobayashi

Yamori

2000

Clin Exp Pharma Physio

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SUMMARY Linkage studies have revealed quantitative trait loci (QTL)for blood pressure in the rat genome using genetic hypertensive rat models. To identify the genes responsible for hypertension, the construction of congenic rats is essential.2. To date, several congenic strains have been obtained from spontaneously hypertensive or Dahl salt-sensitive rats. The results of these studies should be interpreted according to whether the rats carry the whole QTL region or not.3. After establishing congenic strains, three strategies are possible: (i) an orthodox positional cloning in which, using subcongenic strains, the QTL region is cut down to smaller fragments suitable for physical mapping; (ii) a positional candidate strategy in which candidate genes in the QTL regions are studied; or (iii) physiological studies in which intermediate phenotypes directly associated with the hypertension gene are explored. Several other experimental strategies are also available using congenic strains as new animal models for hypertension.4. To make the most of advances in DNA technology, the precise evaluation of the phenotypic difference between congenic strains carrying different QTL or between a congenic and parental strain is critical.

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Successful Isolation of a Rat Chromosome 1 Blood Pressure Quantitative Trait Locus in Reciprocal Congenic Strains

Cited by 45 publications

References 54 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

Genetic Background Determines the Extent of Atherosclerosis in ApoE-Deficient Mice

Congenic Rats For Hypertension: How Useful Are They For The Hunting Of Hypertension Genes?

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