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(Hypertension. 2003;41:847.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Microarray Analysis of Rat Chromosome 2 Congenic Strains

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

From the BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow, Scotland.

Correspondence to Prof Anna F. Dominiczak, BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow, G11 6NT, Scotland. E-mail ad7e{at}clinmed.gla.ac.uk

	Abstract

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Human essential hypertension is a complex polygenic trait with underlying genetic components that remain unknown. The stroke-prone spontaneously hypertensive rat (SHRSP) is a model of human essential hypertension, and a number of reproducible blood pressure regulation quantitative trait loci have been found to map to rat chromosome 2. The SP.WKYGla2c* congenic strain was produced by introgressing a region of rat chromosome 2 from the normotensive Wistar Kyoto (WKY) strain into the genetic background of the SHRSP. Systolic and diastolic blood pressures were significantly reduced in the SP.WKYGla2c* compared with the SHRSP parental strain (198/134±6.1/3.3 versus 172/120±3.8/3.4 mm Hg; F=15.8/8.1, P=0.0009/0.013). Genome-wide microarray expression profiling was undertaken to identify differentially expressed genes among the parental SHRSP, WKY, and congenic strain. We identified a significant reduction in expression of glutathione S-transferase µ-type 2, a gene involved in the defense against oxidative stress. Quantitative reverse transcription–polymerase chain reaction relative to a ß-actin standard confirmed the microarray results with SHRSP mRNA at 8.56x10^-4 ±1.6x10^-4 compared with SP.WKYGla2c* 3.67x10^-3±2.8x10^-4 (95% CI -3.9x10^-3 to -1.8x10^-3; P=0.0034) and WKY 4.03x10^-3±5.1x10^-4; (95% CI -5.4x10^-3 to -8.9x10^-4; P=0.027). We also identified regions of conserved synteny, each containing the Gstm2 gene, on mouse chromosome 3 and human chromosome 1.

Key Words: genetics • hypertension, genetic • gene expression • rats, stroke-prone SHR

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Essential hypertension is a complex polygenic trait. It has been established that genetic determinants contribute between 30% and 50% of the blood pressure variation among individuals. Despite major recent advances in genome sequencing and statistical tools, the genetic dissection of essential hypertension still provides a formidable challenge.¹ However, experimental models of genetic hypertension, which can be considered a reductionist paradigm for human disease, can be used to facilitate the identification of causative genes.

The stroke-prone spontaneously hypertensive rat (SHRSP) is a well-characterized experimental model for human essential hypertension. Similar to human disease, the genetic determination of blood pressure variation in this model is complex and due to multiple gene-gene and gene-environment interactions. The SHRSP develops a number of vascular complications, including cardiac hypertrophy, cardiac failure, and stroke.^2–4 Genome-wide linkage studies have proved successful in the localization of large chromosomal regions containing quantitative trait loci (QTLs) for blood regulation in the SHRSP.⁵ In particular, previous work in our laboratory has identified at least 2 blood pressure QTLs mapping to rat chromosome 2.⁶ This region of chromosome 2 is a classic example of a common or overlapping QTL, as it has been implicated in several crosses.⁷ Moreover, the QTL contained in the telomeric region of rat chromosome 2 has been confirmed in 2 different congenic strains by introgressing the relevant region from Milan normotensive rat or Wistar Kyoto rat (WKY) into the Dahl salt-sensitive background.^8–10

Congenic strains derived from hypertensive rat models have been used to confirm the existence of several other QTLs, and 1 locus has already been fine-mapped to a 0.54-centimorgan (cM) interval.¹¹ However, the requirement for the construction of minimal congenic strains may be circumvented, at least in some cases, by use of new technology such as high-throughput microarray expression profiling. Microarrays are available in 2 principle forms: complementary DNA (cDNA)¹² and oligonucleotides.¹³ Microarray technology has been used to accelerate gene identification by Aitman et al,¹⁴ who used cDNA microarrays and rat chromosome 4 congenic strains to identify Cd36, a gene responsible for defective fatty acid metabolism in the spontaneously hypertensive rat (SHR).

Several mapping studies investigating genome conservation at the genetic and physical level have determined that gene order is relatively invariant showing conserved synteny between mammals.¹⁵ Comparative genome analysis of rat, mouse, and human can be used to identify regions of the human genome likely to harbor genes involved in blood pressure regulation.^7,16 Julier et al¹⁷ and Baima et al¹⁸ provided first successful examples of comparative mapping in which a region involved in blood pressure regulation on rat chromosome 10 indicated a susceptibility locus for human hypertension on human chromosome 17q.

Aims of the current study were to generate and phenotype a congenic strain containing a region of rat chromosome 2 from the normotensive WKY strain introgressed into the genetic background of the SHRSP. Genome-wide expression profiling was undertaken to identify differentially expressed genes among the parental SHRSP, WKY, and congenic strain. Furthermore, a comparative genome analysis was used to identify regions of conserved synteny on mouse and human chromosomes.

	Methods

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Production of Congenic Strains and Blood Pressure Measurements
Inbred colonies of SHRSP and WKY have been developed at the University of Glasgow since 1991, as we previously described.¹⁹ From weaning, all rats have been maintained on normal rat chow (rat and mouse No.1 maintenance diet, Special Diet Services). The congenic strain used in the present study contains a 22-cM segment transferred from WKY (donor strain) to the genetic background of SHRSP (recipient strain) using a marker-assisted "speed" congenic strategy.²⁰ The nomenclature of the strains consists of the first abbreviation belonging to the recipient strain and the second to the donor: Gla denotes that strains originate from the Glasgow colonies, and the number 2 refers to rat chromosome 2. Thus, the congenic strain described in the current study is the SP.WKYGla2 (D2Wox9-D2 Mgh12) and is abbreviated to SP.WKYGla2c* for simplicity.

The Dataquest IV telemetry system (Data Sciences International) was used for the direct measurement of systolic and diastolic blood pressure.^19,20 Briefly, rats were implanted at 12 weeks of age with 1-week recovery followed by 3 weeks of baseline measurements. Rats were killed at the end of the 15th week, and kidneys, spleen, and liver were snap-frozen in liquid nitrogen and stored at -70°C for either RNA or DNA extraction. Genomic DNA was isolated from a 4-mm tip from the tail of congenic animals and genotyping as we described previously.²⁰ These studies were approved by the Home Office according to regulations regarding experiments with animals in the United Kingdom.

Genetic Linkage and Radiation Hybrid Maps
Genotyping was performed by polymerase chain reaction (PCR) amplification of microsatellite markers, and the genotypic results obtained were mapped relative to each other using the MAPMAKER/EXP 3.0 computer package with an error-detection procedure.²¹ We constructed a genetic linkage map of rat chromosome 2 consisting of 74 markers polymorphic between the WKY and SHRSP strains. Genetic distances were calculated with the Haldane mapping function. PCR was performed using the rat genome T55 radiation hybrid (RH) panel obtained from Research Genetics. Scored consensus data were submitted to the RHMAPPER program (http://rgd.mcw.edu/RHMAPSERVER/).

Gene Expression Profiling
Affymetrix GeneChip expression analysis was used to identify differentially expressed probe sets (representing unique gene or expressed sequence tag sequence on the Affymetrix GeneChip) between SHRSP, SP.WKYGla2c*, and WKY. Whole kidneys were homogenized and total RNA extracted from 3 rats from each strain by using the maxi RNeasy kit according to manufacturer’s protocol (Qiagen). Biotinylated amplified target cRNA was prepared and hybridized to the Affymetrix Rat U34 array set (chips U34A, U34B, and U34C; a total of 26 379 probe sets) as described by Affymetrix.²² After hybridization, microarray chips were washed, stained, and scanned. Using MAS 5.0 (Affymetrix) and each of the raw data probe sets, a perfect match versus mismatch value was calculated, and the data were compiled into one value for each probe set. Statistical tools available from Genespring 4.1 (Silicon Genetics) were used to normalize the chip data and identify differentially expressed probe sets among SHRSP, SP.WKYGla2c*, and WKY. Probe sets were identified as being differentially expressed by using the global error model, a variance components model. The final step in the filtering process was to remove genes and expressed sequence tags not expressed in either of the strains being compared.

Quantitative Reverse Transcription–PCR
RNA was accurately quantified using Ribogreen (Molecular Probes) and normalized to 285 ng/µL. Normalization was confirmed by performing real-time reverse transcription (RT)–PCR on the LightCylcer (Roche) of ß-actin (Promega) with comparable threshold cycles. RT-PCR was performed on 3 individual animals from each strain with 0.5 µmol/L each primer for glutathione S-transferase µ-type 2 (Gstm2) F 5'-TTT GAG CCC AAG TGC CTG GA-3' R 5'-GCAGGATCCAATGTGGACAG-3' and then expressed relative to the ß-actin standard curve generated by using serial dilutions (10⁰, 1x10^-1, 5x10^-2, 1x10^-2). Melting curve analysis was performed to confirm the presence of a single species. Concentrations of gene transcripts were calculated based on this standard curve.

Comparative Genome Analysis
Comparative genome analysis used publically available rat, mouse, and human data to identify genes with interspecies sequence identity (homology) for comparative map construction. The anchors for the comparative map are genes that have been mapped in all 3 species. Only genes that could be confirmed as mapping correctly in at least 2 of the species were added to the map.

Statistical Analysis
Blood pressure comparisons between the congenic and the parental strains were performed as previously described.⁹ Microarray data used the global error model, which is a variance components method that estimates both measurement and sample-to-sample variation and standard errors to compare mean expression levels between groups of samples. A nominal significance level of P=0.05 was taken to be the threshold for differential expression. Statistical analysis of RT-PCR by LightCycler was undertaken using the Student t test.

	Results

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Congenic Strain Construction and Phenotyping
The congenic strain SP.WKYGla2c* was produced by introgressing regions of rat chromosome 2 from WKY into the recipient SHRSP strain (Figure 1). Five backcrosses were required to produce the congenic strain with no detectable heterozygosity of background markers. The SP.WKYGla2c* strain incorporated only the lower blood pressure QTL on rat chromosome 2.¹² The SP.WKYGla2c* rats had an average reduction in systolic and diastolic pressures of 20 and 15 mm Hg, respectively when compared with the parental SHRSP strain (198/134±6.1/3.3 versus 172/120±3.8/3.4 mm Hg; F=15.8/8.1, P=0.0009/0.013). Weekly averaged daytime and nighttime systolic and diastolic blood pressures measured over a 3-week period are shown in Figure 2.

View larger version (57K): [in this window] [in a new window]   Figure 1. Rat chromosome 2 congenic strains, in which SHRSP is the recipient and WKY the donor strain (center), and genetic and RH maps (left and right, respectively). Markers shown in bold are placed within the framework RH map. SP.WKYGla2a and SP.WKYGla2b are previously published strains.12 SP.WKYGla2c* strain contains only the lower QTL. Light gray bars represent the regions transferred; dark gray bars, the area of recombination; and black bars, recipient strain genotype.

View larger version (21K): [in this window] [in a new window]   Figure 2. Daytime (D, open symbols) and night-time (N, closed symbols) average systolic blood pressure (A) and diastolic blood pressure (B) recorded by radiotelemetry over a 3-week period in the SHRSP (n=9), SP.WKYGla2c* (n=11), and WKY (n=8) strains; parental SHRSP versus WKY (198/134±6.1/3.3 versus 140/102±2.7/2.0 mm Hg; F=101.0/77.2, P=4.7x10-8/7.9x10-7), SHRSP versus SP.WKYGla2c* (198/134±6.1/3.3 versus 172/120±3.8/3.4 mm Hg; F=15.8/8.1, P=0.0009/0.013).

Construction of Genetic and RH Maps
To create the new genetic linkage map, a total of 74 microsatellite markers, spanning rat chromosome 2, were genotyped in F2 animals. Of the 74 markers scored, we positioned 55 on the RH map of rat chromosome 2. Nineteen of the markers added to the map did not position within the region of rat chromosome 2, as they were multilinked and the reduction of stringency to accommodate them would result in a less accurate map. The markers covered a distance of 1224 centiRays and were all placed with a logarithm of odds ratio (LOD) >10. This equates to 10¹⁰ odds for linkage.

Gene Expression Profiling
Total numbers of differentially expressed genes between the SHRSP and SP.WKYGla2c*, as well as the SHRSP and WKY, are shown in Table 1. Of the 45 differentially expressed probe sets in the SHRSP and SP.WKYGla2c* comparison, 12 were also identified in the SHRSP and WKY comparison (Table 2). Four of these probe sets have a known rat chromosomal location, with 3 mapping to the congenic segment. All 3 probe sets that mapped to the congenic segment represented the same gene, glutathione S-transferase µ-type 2 (Gstm2). Of these, two were gene probe sets, and one was an expressed sequence tag DNA sequence. Quantitative RT-PCR relative to the same ß-actin standard curve further confirmed the microarray results (Figure 3). The LightCycler showed Gstm2 expression was significantly lower in SHRSP (8.56x10^-4±1.6x10^-4) versus SP.WKYGla2c* (3.67x10^-3±2.8x10^-4); (95% CI -3.9x10^-3 to -1.8x10^-3; P=0.0034) and versus WKY (4.03x10^-3 ±5.1x10^-4); (95% CI -5.4x10^-3 to -8.9x10^-4; P=0.027).

View this table: [in this window] [in a new window]   TABLE 1. Differentially Expressed Genes Identified by Global Error Model Filtering Technique in Paired Comparisons Between the Congenic and Parental Strains

View this table: [in this window] [in a new window]   TABLE 2. Microarray Data for Probe Sets in Common for SHRSP and SP.WKYGla2c*, and SHRSP and WKY Comparisons

View larger version (41K): [in this window] [in a new window]   Figure 3. A, Representative Affymetrix gene chip images for the 16 perfect match (upper) and mismatch (lower) probe set oligonucleotides for Gstm2 (X04229) from each of the WKY, SP.WKYGla2c*, and SHRSP strains, showing decreased levels of Gstm2 expression in SHRSP. B, Graph depicting the accumulation of fluorescence throughout the PCR for Gstm2; SHRSP (8.56x10-4±1.6x10-4) versus SP.WKYGla2c* (3.67x10-3±2.8x10-4); (95% CI -3.9x10-3 to -1.8x10-3; P=0.0034) and versus WKY (4.03x10-3±5.1x10-4); (95% CI -5.4x10-3 to -8.9x10-4; P=0.027). Inset graph indicates the ß-actin standard curve.

Comparative Genome Analysis
We used publically available databases to demonstrate that the SP.WKYGla2c* congenic segment showed highly conserved synteny to mouse chromosome 3 and human chromosome 1. Orthologous genes between the 3 species are shown in Figure 4. Gstm2 is one of the orthologs, as it maps to the region of conserved gene synteny in all 3 species.

View larger version (34K): [in this window] [in a new window]   Figure 4. The comparative genome analysis of defined region within the SP.WKYGla2c* segment. All map distances are in centiRays (cRays): rat chromosome 2 (left), mouse chromosome 3 (center), and human chromosomes 1 (right). Gstm2 maps to a corresponding region in all 3 species.

	Discussion

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Using a combination of congenic strategy and microarray DNA chip technology, we identified Gstm2 as a putative positional and physiological candidate gene within the blood pressure QTL on rat chromosome 2. Furthermore, we used a comparative genome analysis and identified mouse and human orthologs on chromosomes 3 and 1, respectively. Gstm2 was significantly downregulated in the SHRSP compared with both SP.WKYGla2c* and WKY strains by using microarray gene expression profiling, and these results were confirmed by quantitative RT-PCR. Gstm2 belongs to a large gene family encoding glutathione S-transferases, which catalyze the conjugation of electrophilic compounds to glutathione, thus playing a prominent role in cellular resistance against oxidative stress.²³ This is of physiological and pathophysiological significance in the SHRSP, as we have shown that the endothelial dysfunction in this model is owing to increased vascular oxidative stress largely accounted for by the increased generation of superoxide anion.^24–26 Moreover, the induction of chronic oxidative stress by glutathione depletion has been shown to cause severe hypertension in normotensive rats.²⁷ There is also some evidence for similar mechanisms in human endothelial dysfunction and essential hypertension.^28,29 Although an alternative explanation may be that changes in the levels of Gstm2 expression between the strains are secondary to blood pressure differences already present in 15-week-old rats.

Other efforts to analyze the QTLs on rat chromosome 2 have focused on the construction of overlapping congenic strains to narrow down the region(s) under study.^8–10 However, these studies have not resulted in the identification of positional candidate genes. Although theoretical considerations have suggested that it should be possible to obtain minimal congenic strains as small as 1 cM,⁵ this has been proven very difficult in practice. In the current study, we produced dense genetic and RH maps of rat chromosome 2 in an effort to narrow down the congenic region. Similar work has been performed for the remaining rat chromosomes by other groups.^30,31 However, it seems unlikely that minimal congenic strains encompassing <3 cM will be frequently produced. Therefore, ancillary strategies such as microarray gene expression profiling might contribute to causative gene discovery. Aitman et al¹⁴ and Eaves et al³² used rat and mouse congenic strains, respectively, in combination with gene chip technology. The former study¹⁴ identified a strong positional and physiological candidate gene, the Cd36, although the congenic interval of the SHR.BN strain used was relatively large at 36 cM. However, Eaves et al³² failed to identify any strong candidates, despite a true minimal congenic strain at 0.35 cM. These contrasting results, together with the microarray data from the current study, confirm that although not every congenic/microarray experiment will identify causative genes, the size of congenic interval should not be seen as a limitation for a well-designed microarray experiment.

The choice of tissue for gene expression profiling has been a matter of recent debate.³³ It seems that for gene hunting experiments in hypertension, the kidney is an ideal choice as several elegant transplantation experiments showed that hypertension always "travels with the kidney."^34–36 The other important issue, already stressed by Aitman et al¹⁴ but also clearly seen in the current study, is the relative ease of interpretation of microarray data. Although one would expect hundreds of differentially expressed genes between the 2 parental strains, this number is significantly reduced in the congenic and parental strain comparisons. Moreover, initially one would focus on genes that are differentially expressed and mapped to the congenic region, with a possibility of later analysis of genes mapping to other chromosomes but perhaps still of functional importance through the relevant physiological pathways.³⁷

Perspectives
We have identified Gstm2 as a positional and physiological candidate gene for blood pressure regulation and oxidative stress in the SHRSP. Using comparative genome analysis between rat, mouse, and human, we successfully transferred the relevant QTL across species and showed that the rat Gstm2 has orthologs on mouse chromosome 3 and human chromosome 1. Despite highly significant changes in expression between the congenic and the SHRSP strain, we have not excluded the possibility that these could be secondary to blood pressure differences. Further studies in young animals during the development of hypertension may help elucidate primary mechanisms.

	Acknowledgments

 
This work was funded by the British Heart Foundation Program (PG/97009) and Project (PG2000023) grants and the Wellcome Trust Functional Genomics Initiative (066780). We thank Dr Neil Hanlon for bioinformatic support, Dr Catriona Young for microarray assistance, and Dr Ping Ye for advice on quantitative RT-PCR. We also thank Margaret Cunningham and Andy Carswell for excellent technical support.

	Footnotes

 
Drs McBride and Carr contributed equally to this work.

Received October 4, 2002; first decision October 24, 2002; accepted November 4, 2002.

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