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(Hypertension. 2005;45:698.)
© 2005 American Heart Association, Inc.

Original Articles

Combined Genealogical, Mapping, and Expression Approaches to Identify Spontaneously Hypertensive Rat Hypertension Candidate Genes

From the Institute of Molecular Medicine (C.A.H., E.B., M.F., P.A.D.) and Human Genetics Center (E.B.), University of Texas Health Science Center, Houston.

Correspondence to Peter A. Doris, PhD, Institute for Molecular Medicine, University of Texas Health Science Center, 2121 Holcombe Blvd, Houston TX, 77030. E-mail peter.a.doris{at}uth.tmc.edu

	Abstract

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Allelic expression in genes has become recognized as a heritable trait by which phenotypes are generated. We have examined gene expression in the rat kidney using genome-wide microarray technology (Affymetrix). Gene expression was determined across 4 rat strains, 3 hypertensive spontaneously hypertensive rat (SHR) substrains (SHR-A3, SHR-B2, and SHR-C), and a normotensive strain (Wistar-Kyoto [WKY]). Expression measurements were made in multiple animals from all strains at 4 time points (4 weeks, 8 weeks, 12 weeks, and 18 weeks of age), covering the prehypertensive period in SHR (4 weeks), and the period of rapidly rising blood pressure (8 and 12 weeks) and of sustained hypertension (18 weeks). Regression analysis revealed a close relationship across all strains during the first 3 time points, after which SHR-A3 became a substantial outlier. SHR-B2 and SHR-C demonstrated a very close relationship in gene expression at all times but also showed increased differences compared with the other strains at 18 weeks of age. We identified genes that were consistently different in expression, comparing all SHR substrains at each time point with WKY. The resulting list of genes was compared with blood pressure quantitative trait loci reported for SHR to refine a number of genes consistently differentially expressed between SHR substrains and WKY, persistently differentially expressed across multiple time points, and located in SHR blood pressure–determinative regions of the genome. Genealogical relationships and SHR substrain intercrosses suggest that genes responsible for heritable hypertension in SHR are shared across SHR substrains. The present approach identifies a number of genes that may influence blood pressure in SHR by virtue of allelic effects on gene expression.

Key Words: hypertension, genetic • gene expression • kidney • genes

	Introduction

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Heritable variation in gene expression is a key evolutionary force by which species diverge.^1–4 Within species, there is also extensive evidence for heritable allelic effects on gene expression.^5,6 Indeed, extrapolation across the entire human genome of the frequencies of known coding sequence and regulatory sequence polymorphisms suggest that regulatory polymorphisms contribute more to interindividual variation than coding sequence polymorphisms.³ In addition to the creation of Mendelian traits, such heritable gene regulatory effects may contribute importantly to the creation of polygenic disease phenotypes, including hypertension. For example, evidence implicating the angiotensinogen gene in h uman hypertension emphasizes the role of gene haplotypes, including functional polymorphisms in the promoter region of the gene that have been shown to influence angiotensinogen gene transcription and associate with plasma angiotensinogen levels.^7,8

Positional (linkage mapping) and association approaches to resolving the heritable basis of polygenic disease susceptibility face substantial obstacles to the identification of loci and gene variants consistently shown to associate with disease susceptibility.^9,10 In spite of a decade of effort, resolution of the genetic basis of susceptibility to essential hypertension at the level of single genes is limited and findings are often inconsistent. The same conditions characterize studies of animal models of heritable hypertension even though they offer more favorable investigative opportunities than outbred human populations, such as reduced genetic heterogeneity, controlled breeding, and greater scope for interventional study. Given the important role of heritable effects on gene expression in the creation of intraspecies phenotypes and the availability of comprehensive gene expression assessment tools, expression genetics may have matured sufficiently to combine constructively with positional genetics to contribute to resolution of the allelic basis of heritable hypertension.

The purpose of the present study was to investigate the capacity of comprehensive gene expression arrays to identify genes differing in their level of expression between Wistar-Kyoto (WKY) normotensive rats and 3 spontaneously hypertensive rat (SHR) substrains. These SHR substrains are descended from the same pair of F₀ parents and were inbred through F₈ before isolation of substrains.¹¹ This genealogy suggests that hypertension-causing alleles are likely to extensively overlap among SHR substrains. The shared genetic basis of hypertension in SHR substrains is supported by blood pressure (BP) measurements from F₂ progeny of SHR substrain crosses,^12,13 which indicate that F₂ progeny have similar BP levels and similar levels of BP variance as the parental substrains. This observation indicates that each SHR substrain is analogous to a multiple congenic strain. In each substrain, genomic regions not containing hypertension-permissive or causative alleles may differ, but regions harboring alleles involved in hypertension are shared across substrains and do not segregate. Comparison of multiple SHR substrains can be used to identify heritable expression phenotypes common to all substrains, which persist across multiple developmental time points (prehypertensive and hypertensive) and are therefore likely to be attributable to cis effects on gene expression and not to the effect of hypertension or other developmental effects on gene expression. Comparison of multiple SHR substrains with a normotensive reference strain (WKY) can enhance analytical power compared with a contrast between 2 strains.

	Methods

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Animals and Measurements
Studies were performed on 4-, 8-, 12-, and 18-week-old male animals. We used WKY and SHR-A3 rats of the Heidelberg substrains that have been maintained in our facility for 8 years. SHR-B2 and SHR-C stocks were generously provided to our laboratory in 2002 by Professor T. Suzuki (Kinki University School of Medicine, Kinki, Japan) and are descended from the original substrains reported by Okamoto.¹¹ All animals used in the studies were produced in our breeding program and housed under controlled conditions in an Association for Assessment and Accreditation of Laboratory Animal Care–approved animal facility. Animals were provided a standard rodent chow diet and drinking water ad libitum.

For tissue collection, animals were anesthetized by isoflurane inhalation, and kidneys were rapidly dissected via ventral laparotomy. Renal gene expression analysis was performed using total RNA preparations from axial renal segments including cortex and medulla. Ureteric pelvis and major vascular structures of the renal sinus were removed from the sample. Three or 4 animals from each strain were used at each time point to permit all gene expression measurements to be statistically analyzed. Each sample from each animal was treated as an independent sample, and no pooling was performed.

Transcript Profiling
Transcript abundance was determined as reported previously by us¹⁴ using the Affymetrix rat RG-U34A array containing probe sets for 5288 rat genes and 3452 rat expressed sequence tags (ESTs) following manufacturer-recommended protocols. Most genes on this array are interrogated by probe sets comprising 16 unique 25-mer oligonucleotides. Adjustment for nonspecific fluorescence is made using hybridization data from 16 further oligonucleotides per probe set that are identical except at a single base residue in the middle of the oligonucleotide. Expression levels are reported as mean±SEM. A nominal P value of 0.05 was considered statistically significant for the purposes of comparison across strains (Mann–Whitney test). This data set has been deposited in the NCBI Gene Expression Omnibus (GEO database) with series accession number GSE2104 (release date April 1, 2005).

	Results

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To assess overall changes in gene expression across time and across strains, we performed regression analyses to examine the relationships among data sets. Table 1 shows the R-square values of regressions examining each strain across specific time points. During the initial 3 time points, overall WKY and SHR-A3 gene expression is more closely related than is expression in WKY to either SHR-B2 or SHR-C substrains. However, at 18 weeks of age, there is a dramatic reduction in the relationship between renal gene expression in SHR-A3 and WKY so that patterns of expression in SHR-B2 and SHR-C are more similar to WKY at this time point. Interestingly, there is also a substantial decline in relationship at 18 weeks of age between gene expression in SHR-A3 and SHR-B2, as well as between SHR-A3 and SHR-C. The R-square values across time indicate a close relationship between renal gene expression in strains SHR-B2 and SHR-C.

Table 2 provides further insight into the relationship within strains of the pattern of gene expression. Here again, the most notable feature observed is that SHR-A3 gene expression at 18 weeks is substantially different from gene expression in SHR-A3 at other times. In contrast, there is almost no change in the relationship between gene expression at 18 weeks and expression at other time points in SHR-B2 and SHR-C. Together, Tables 1 and 2 suggest major changes in gene expression in SHR-A3 occurring at 18 weeks that distinguish this strain from both of the other SHR substrains, as well as from WKY.

Table 3 indicates individual genes and ESTs represented on the array that show persistent differences across time when all SHR substrains are contrasted with WKY animals. The chief rationale of this study is that the genealogical relationships among SHR substrains create, in effect, multiple congenic substrains in which hypertension permissive and causative alleles are shared across substrains and are interspersed among background genomic variation arising from their shared ancestors and unrelated to hypertension. Thus, genes involved in the genesis of hypertension that act via heritable alterations in gene expression may be identified among those that share consistent differences in expression between WKY and all SHR substrains.

Because our hypothesis also allows that some background genes unrelated to hypertension will also be shared across the hypertensive substrains, we sought to refine the list of differentially expressed genes by identifying those among them that are located in chromosomal regions implicated by studies seeking to define BP quantitative trait loci (QTLs) in SHR. We identified 14 genes and ESTs representing 8 chromosomes and 11 SHR BP QTLs. Figure 1 indicates the chromosomes containing these genes and ESTs and their position on the chromosomes. These genes and ESTs have mean expression levels across the SHR substrains that range from 5.4-fold to –3.9-fold different from WKY.

View larger version (36K): [in this window] [in a new window]   Figure 1. Consistently differentially expressed genes and ESTs that map to SHR BP QTLs. The chromosome position of the gene or EST is indicated by an arrow to the left of the chromosome; the gene or EST is labeled next to this arrow, and citations indicating localization of SHR BP genes in this chromosome/region are indicated below the gene/EST identification. Thin vertical lines represent the extent of BP QTLs observed in freely segregating crosses. Wide, shaded lines represent congenic segments27,28,33–38 that have been isolated in or from SHR and shown to affect BP.

	Discussion

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SHR substrains are the progeny of a pair of animals selected from an outbred Wistar colony on the basis of their BP.^11,15 Further selective inbreeding through 8 generations resulted in the production of rats with high levels of BP (Figure 2).¹⁵ Assuming a coefficient of inbreeding in the parental animals of 0, by F₈, this coefficient would reach 0.8, resulting in a high degree of relatedness among members of the F₈ generation and a substantial loss of heterozygosity. The resulting concentration of adverse alleles may result in reduced fitness and fertility, consequently breeding programs seeking to generate fully inbred lines generally initiate multiple sublines around F₈ to F₁₀ in the anticipation that some sublines may extinguish with further inbreeding. The SHR substrains studied here are derived from this pattern of selective inbreeding. Each shares common ancestors not only in the outbred parental (F₀) generation but also in later generations before F₈. Indeed, the SHR-B2 and SHR-C substrains are even more closely related to one another: SHR-B2 animals are all derived from a brother–sister pair in the F₁₄ generation, whereas SHR-C are derived from a line arising from the same F₁₄ parents, subsequently crossed with progeny sharing the same parents as the SHR-B2 strain in the F₁₁ generation.¹¹ Thus, there is a high degree of allele sharing among these hypertensive substrains arising from common ancestors within the inbreeding program. There is also allele sharing with WKY. Although this strain originated from the same colony, a different pair of founders and selection for normal BP levels was used.¹⁵

View larger version (20K): [in this window] [in a new window]   Figure 2. Genealogical relationships among SHR substrains used in the present study (modified from Okamoto et al11).

Analysis of the relationship among gene expression patterns across time within strains and across strains at various times yields strong evidence of heritable influence on gene expression (Tables 1 and 2). Based on genealogy, the strains expected to have the closest genetic relationship, SHR-B2 and SHR-C, show a remarkably close relationship in their patterns of gene expression. Published genealogical records do not permit a precise determination of the last generation in which SHR-A3 shared common parents with SHR-B2 and SHR-C.¹¹ However, genealogical information summarized in Figure 2 indicates this occurred at some point between the F₁ and F₈ generations, when coefficients of inbreeding are rising rapidly from initial levels. Because SHR-B2 and SHR-C have common ancestors in the F₁₁ and F₁₄ generations of inbreeding, they are more closely related, and this close genetic relationship is the likely force determining the high similarity in patterns of gene expression in these strains (Table 1). The overall degree of relationship in gene expression between WKY and the 3 SHR substrains is quite similar but is marked by a substantial reduction at 18 weeks. This is greatest for SHR-A3 and might reflect the increased susceptibility of this strain to hypertensive end organ injury.

We inferred from genealogy a common genetic basis for hypertension across SHR substrains.¹¹ This has been proven by the intercrossing of SHR substrains to generate a freely segregating F₂ intercross. Two independent studies indicated that BP levels in the F₂ progeny of SHR substrain intercrosses (SHR-A3 [stroke prone]xSHR [stroke resistant]¹³ and SHR-A3xSHR-C¹²) overlapped the parental strains and that F₂ BP variance was also similar to parental strain variance. If these substrains had fixed different hypertension alleles, then some members of the F₂ generation would inherit less than a full complement of hypertension alleles, and consequently, BP variance in the F₂ generation would be increased and mean F₂ BPs would be substantially lower than parental strain pressures. Neither was observed, producing a high likelihood that alleles generating hypertension are largely shared across SHR substrains. Thus, we reasoned that genes contributing to hypertension via alleles that confer heritable influences on gene expression might be brought to light by comprehensive gene expression studies contrasting SHR with the normotensive WKY control strain. Many alleles that affect gene expression but do not affect BP may also be differentially fixed in such a contrast. However, comparison of multiple hypertensive substrains with the control strain may increase the power of the analysis. Further increase in power may be obtained by seeking genes that show persistent expression differences across several time points. Such genes may be more likely to reflect cis-determined allelic control of gene expression in which a regulatory effect of allelic variation resides within or near the gene and affects expression in a way that is fixed with respect to time. However, it is also possible that genes in Table 3 include genes, the expression of which is controlled by heritable differences in trans-acting regulation. Mapping studies would reveal whether control arises in cis or in trans.

The investigative paradigm we used seeks to exploit genealogical information, mapping information, and heritable influences on gene expression that may yield new insight into the genetic basis of heritable hypertension. Among genes found consistently differentially expressed in all SHR substrains compared with WKY, some interesting candidates emerge for which existing information permits some level of interpretation. For example, we reported previously that Ephx2 is differentially expressed between SHR-A3 and WKY and that this is attributable to gene polymorphism associated with cis effects on gene expression, the influence of which extends to protein abundance and activity of the encoded enzyme. However, we eliminated this gene from further consideration as a hypertension gene because no association between inheritance of the SHR-A3 Ephx2 allele and BP could be demonstrated in the F₂ progeny of an SHR-A3xWKY cross and because another SHR substrain (SHR/N Criv) possesses the same allele as WKY.¹⁴ In the present study, persistent differential Ephx2 expression was observed across the 3 SHR substrains examined when compared with WKY. However, the Ephx2 gene does not localize to a known SHR BP QTL. Thus, F₂ intercross and gene expression approaches in substrains concur in eliminating this gene from further investigation as a hypertension gene.

The Sa gene was initially identified as a gene highly differentially abundantly expressed in kidney.¹⁶ Our analysis finds that this difference is sustained across the 3 SHR substrains examined. This gene has been thoroughly studied because of its differential expression, its position in a well-substantiated SHR BP QTL,^17–21 evidence of polymorphism in the Sa locus between SHR and WKY,^22,23 and evidence from human studies suggesting involvement in BP determination.^24–26 Recent rat congenic studies have not found support for the involvement of Sa in BP regulation.^27,28 Similarly, efforts to investigate the functional relationship of the Sa gene to BP using a mouse knock-out model were not fruitful,²⁹ although gene ablation is not a robust analogy of the increased allelic Sa gene expression in SHR.

A further, ongoing phase of the studies reported here involves characterizing sequence variation between differentially expressed genes. In addition to the characterization of Ephx2 described above, we have now completed polymorphism analysis and parental strain genotyping for 4 of the genes identified in Table 3. In each case, between 1 and 4 single-nucleotide polymorphisms were identified in the coding, proximal 5' regulatory, or flanking intronic sequence (data not shown). In each case, all SHR substrains tested shared the same genotype but differed from WKY. The same genotype was also identified in the commercial SHR substrain SHR/N Criv. This consistent pattern in genotype:phenotype relationship of these expression candidate genes strengthens the rationale to investigate further the allelic basis of differential gene expression in SHR and the involvement of these alleles in hypertension.

Although current gene expression arrays permit the simultaneous analysis of many thousands of rat genes and ESTs, this method is not yet capable of addressing all functional genes in the genome. Consequently, the genes in Table 3 probably represent an incomplete list of genes demonstrating persistent differences in expression between SHR and WKY. However, as rat genome annotation progresses and arrays continue to improve in their extent of genomic coverage, a more complete analysis should be possible. Our findings to date indicate that the approach we have taken can identify genes that are consistently differentially expressed between SHR substrains and WKY, that these genes are, in every case thus tested, allelic variants, and that these genes can be filtered to include those resident in genomic regions implicated in BP determination in SHR. This result is a gene-directed approach to resolving the basis of the polygenic hypertension in SHR. It contrasts from position-directed approaches such as F₂ QTL mapping and congenic strain analysis that must confront important obstacles to locus refinement related to the infrequency and nonuniform nature of recombination. Indeed, comprehensive gene expression approaches have recently been introduced to congenic strain analysis as a means to overcome the difficulty of narrowing the isolated chromosomal region to a manageable number of genes.^30–32

Continuing efforts to analyze the allelic structure of these genes are under way and provide a means to advance this approach to the next level: assessment of whether coding sequence variation occurs in conjunction with regulatory variation, assessment of the implications of gene variation on function, confirmation of the allelic nature of gene expression differences in F₂ progeny of an SHRxWKY cross, and assessment of the association of allelic variation with BP in the F₂ progeny.

Perspective
In the present study, we combined genealogical elements incorporated in the selective breeding of SHR substrains with genome-wide gene expression studies seeking to identify genes that are consistently differentially expressed across multiple SHR substrains when compared with a normotensive reference strain and that are persistently differentially expressed over multiple time periods during the development of hypertension. Consistence in expression differences across SHR substrains suggests that the genes may be contributing to hypertension because of the shared allelic basis of hypertension among these substrains. Persistence across time suggests cis-determined allelic variation as a likely cause of differential expression, but additional mapping studies are required to test for trans-acting control. By further refining the genes identified with this approach using positional information derived from BP QTL mapping studies in SHR, we reduced this list to 14 genes that may contribute to hypertension because of their differential regulation in SHR. This work proposes a novel paradigm to penetrate the substantial obstacles to resolution of the genetic basis of polygenic hypertension to the level of specific genes, and it exploits animal models in which all necessary causative and permissive gene–gene interactions are preserved. It is limited in being applied to investigate the heritable basis of hypertension only in a single rat model (SHR) of the disease.

	Acknowledgments

 
This work was supported by grants from National Institutes of Health to P.A.D. (DDK45538, to E.B. (HL51021) and to M.F. (NS41466 and HL69126). Rat gene symbols used in this article correspond to those in the NCBI LocusLink and Unigene databases.

Received October 12, 2004; first decision November 9, 2004; accepted January 7, 2005.

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