Microarray Analysis of Rat Chromosome 2 Congenic Strains

McBride, Martin W.; Carr, Fiona; Graham, Delyth; Anderson, Niall; Clark, James S.; Lee, Wai Kwong; Charchar, Fadi J.; Brosnan, M J; Dominiczak, Anna F.

doi:10.1161/01.hyp.0000047103.07205.03

Cited by 77 publications

(69 citation statements)

References 43 publications

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“…Amongst the classes of GST enzymes the mu class is particularly involved in detoxification of free radicals. GSTM enzymes protect against oxidative stress, and or reduced expression of Gstm1 has been found to be associated with hypertension in rats [23,34,35]. This text box shows major mechanisms but is by no means a comprehensive overview of the pathogenesis of hypertension.…”

Section: Oxidative Stressmentioning

confidence: 99%

“…First, WTCCC was the first large-scale genome 24 scan using dense SNP markers across the genome. Previous genome scans were limited by the 25 in SHRSP and chromosome 2 congenic strains [34,35], GSTM genes were subject to association 1 studies in humans [39][40][41] due to the fundamental role of the oxidative stress pathway in 2 cardiovascular pathophysiology [42,43]. While there is agreement on the involvement of genetic 3 variants of GSTMs in the development of cancer [44,45], studies on the role of GSTMs in 4 cardiovascular diseases are less consistent [40,41].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The genetics of cardiovascular disease

Delles¹,

McBride²,

Padmanabhan³

et al. 2008

Trends in Endocrinology & Metabolism

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Section: Oxidative Stressmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The genetics of cardiovascular disease

Delles¹,

McBride²,

Padmanabhan³

et al. 2008

Trends in Endocrinology & Metabolism

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“…The search for differential gene expression has recently received considerable attention as a means of finding candidate genes for QTLs (Liang et al, 2003;McBride et al, 2003;Moujahidine et al, 2004;Garrett et al, 2005;Hubner et al, 2005;Yagil et al, 2005). It is easy to understand the tantalizing appeal of such an approach, because it generates gene candidates directly, rapidly and immediately, with apparent performance differentials.…”

Section: Use Of Heterozygotes As a Deductive Functional Test Of Qtlsmentioning

confidence: 99%

Individual QTLs controlling quantitative variation in blood pressure inherited in a Mendelian mode

Duong

Charron

Deng³

et al. 2006

Heredity

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We studied three possible genotypes at 10 well-defined blood pressure (BP) QTLs using congenic rat lines. The central question was whether the hypertensive or normotensive allele is dominant, or whether there is partial dominance. The congenic strains were employed to investigate the BP effects of alleles originating from normotensive rats in the background of hypertensive Dahl salt-sensitive (DSS) rats. The normotensive alleles at eight QTLs were fully dominant over DSS alleles, which we tentatively interpreted as indicating that DSS rats incurred a loss of function at these loci and that the QTLs produced BP-reducing agents. In contrast, the normotensive allele of only one QTL was recessive over its DSS counterpart, implying a gain of function at this QTL or a null allele involved in generating a BP-elevating agent. Only one locus, C17QTL, had alleles exhibiting partial dominance. These estimates of dominance differ considerably from those obtained by QTL analysis in a F2 cross. This disagreement demonstrates the importance of establishing a cause-effect relationship between a QTL and its phenotypic effect via congenic strains. The dominance relationships suggest pertinent strategies for gene identification and pharmaceutical intervention.

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“…Only a few microarray analyses of the SHR have been published, evaluating adipose tissue, 44 kidney, 45,46 and vascular smooth muscle cells. 47 The adipose tissue study, performed by Aitman et al, 44 was a landmark experiment because microarray data were used to pinpoint the Cd36 gene (fatty acid translocase) as a genetic underpinning of insulin resistance, defective fatty acid metabolism, and hypertriglyceridemia in the SHR.…”

Section: Perspectivesmentioning

confidence: 99%

“…Furthermore, such rat studies usually did not present data on the same genes that we found differentially expressed. A study of chromosome 2 congenic kidneys 45 did, however, find a significant reduction of glutathione S-transferase 2 (Gstm2), a gene involved in the oxidative stress response, and mapped this gene through comparative genome analysis to corresponding regions on rat chromosome 2, mouse chromosome 3, and human chromosome 1. RT-PCR investigation of the adrenal gland of the SHR found a statistically significant 2.5-fold increase of tyrosine hydroxylase expression in the SHR as compared with its normotensive control, the Wistar-Kyoto rat.…”

Section: Perspectivesmentioning

confidence: 99%

Neuroendocrine Transcriptome in Genetic Hypertension

Fries¹,

Mahboubi²,

Mahapatra³

et al. 2004

Hypertension

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Abstract-The genetic basis of hypertension in the genetically/hereditary hypertensive (BPH/2) mouse strain is incompletely understood, although a recent genome scan uncovered evidence for several susceptibility loci. To probe the neuroendocrine transcriptome in this disease model, 12 488 probe set microarray experiments were performed on mRNA transcripts from adrenal glands of juvenile (prehypertensive) and adult BPH/2 (hypertensive), as well as the genetically/hereditary low-blood pressure (BPL/1), strains at both time points. To determine the impact of strain (BPH/2 versus BPL/1), age (juvenile versus adult), and the interaction of strain and age on gene expression levels, we performed standard 2-factor ANOVA and computed a concordance coefficient to assess the reproducibility of gene expression measurements among replicates. Of genes with significant (PϽ0.05) differential expression, 2647 showed strain differences, 982 showed age differences, and 757 exhibited strain-by-age interaction. Fold-changes in gene expression assayed by microarray were confirmed in a subset by real-time polymerase chain reaction (Rϭ0.739, Pϭ0.0094). We used a systems biology approach to evaluate alterations in contributing biochemical pathways and we statistically quantified these global pathway disturbances using the Kolmogorov-Smirnov goodness-of-fit test. We found widespread, indeed global, alterations in patterns of gene expression in diverse systems of BPH/2: in sympathochromaffin transcripts suggesting increased sympathetic stimulation; in vasoconstrictor/vasodilator systems; global reductions in carbohydrate intermediary metabolism; and increases in oxidative stress, with changes in oxygen radical forming and disposition enzymes. These analyses highlight widespread derangements in diverse physiological pathways, providing multiple avenues for further investigation into the pathogenesis of genetic hypertension. Key Words: hypertension Ⅲ genetics Ⅲ adrenal gland Ⅲ gene expression Ⅲ metabolism Ⅲ lipids Ⅲ oxidative stress H ypertension displays substantial genetic influence, with heritability estimates for blood pressure ranging from Ϸ30% to 50%. 1 The multifactorial nature of this condition, however, has made it difficult to elucidate the underlying genetic components. With the advent of gene expression microarray technology, it has become possible to study large numbers of genes in parallel, which is ideal for studying polygenic diseases such as hypertension. 2 High-throughput microarray studies of hypertension are well complemented by the use of genetic models of hypertension. The genetically/hereditary hypertensive "blood pressure high" (BPH/2) mouse was developed by Schlager in a selection program to develop a strain of hypertensive mice inbred to homozygosity. 3 The BPH/2 strain parallels human hypertension, with elevated blood pressure, higher heart rate, and early mortality. 4 Schlager's selection program also included concurrent development of a hypotensive mouse strain, the "blood pressure low" (BPL/1). 3 Although not...

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Microarray Analysis of Rat Chromosome 2 Congenic Strains

Cited by 77 publications

References 43 publications

The genetics of cardiovascular disease

The genetics of cardiovascular disease

Individual QTLs controlling quantitative variation in blood pressure inherited in a Mendelian mode

Neuroendocrine Transcriptome in Genetic Hypertension

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