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(Hypertension. 1999;34:643-648.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Congenic Substitution Mapping Excludes Sa as a Candidate Gene Locus for a Blood Pressure Quantitative Trait Locus on Rat Chromosome 1

Norbert Hübner; Young-Ae Lee; Klaus Lindpaintner; Detlev Ganten; Reinhold Kreutz

From the Max-Delbrück-Center for Molecular Medicine (N.H., Y-A.L., K.L., D.G.), and the Department of Clinical Pharmacology (N.H., D.G., R.K.) and Department of Medicine IV (R.K.), Benjamin Franklin Medical Center, Freie Universität Berlin, Berlin, Germany; the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School (K.L.), Boston, Mass; and the Pharmaceuticals Division of F. Hoffmann-La Roche (K.L.), Basel, Switzerland.

Correspondence to Dr Reinhold Kreutz, Department of Clinical Pharmacology, Benjamin Franklin Medical Center, Freie Universität Berlin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail Kreutz{at}medizin.fu-berlin.de

	Abstract

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Abstract—Previously, linkage analysis in several experimental crosses between hypertensive rat strains and their contrasting reference strains have identified a major quantitative trait locus (QTL) for blood pressure on rat chromosome 1 (Chr 1) spanning the Sa gene locus. In this study, we report the further dissection of this Chr 1 blood pressure QTL with congenic substitution mapping. To address whether the Sa gene represents a candidate gene for the Chr 1 blood pressure QTL, congenic strains were developed by introgressing high blood pressure QTL alleles from the stroke-prone spontaneously hypertensive rat (SHRSP) into the normotensive Wistar-Kyoto (WKY-1) reference strain. Congenic animals carrying a chromosomal segment from stroke-prone spontaneously hypertensive rats between genetic markers Mt1pa and D1Rat200 (including the Sa gene locus) show a significant increase in basal systolic and diastolic blood pressure compared with their normotensive Wistar-Kyoto progenitors (P<0.001, respectively), whereas congenic animals carrying a subfragment of this Chr 1 region defined by markers Mt1pa and D1Rat57 (also spanning the Sa gene) do not show elevated basal blood pressure levels (P=0.83 and P=0.9, respectively). Similar results were obtained for NaCl-induced blood pressure values. Thus, the blood pressure QTL on Chr 1 is located centromeric to the Sa gene locus in a region that is syntenic to human chromosome 11p15.4-p15.3. This region excludes the Sa as a blood pressure–elevating candidate gene locus on the basis of congenic substitution mapping approaches.

Key Words: hypertension, essential • rats, inbred SHR • rats, inbred WKY • genetics • complex traits • crosses, genetic

	Introduction

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Primary hypertension is one of the most common chronic diseases. It represents a major risk factor for cardiovascular morbidity and mortality. Hypertension shows a significant degree of heritability and is commonly recognized as a complex, polygenic disorder with the exception of rare monogenetic forms.^{1 2} The nature of this complex disease makes it difficult to identify contributing genes.² A method to reduce the complexity of hypertension is the use of inbred animal models in the genetic analysis of this disorder. Information on genetic factors identified in such experimental systems may provide insights into disease mechanisms that can subsequently be applied to study human hypertension.

The identification of the Sa gene by Iwai and Inagami³ and the observation of its differential expression pattern in kidneys from hypertensive and normotensive rat models has generated considerable interest over the past few years.⁴ Subsequent to its identification, several investigators have shown that the Sa gene locus cosegregates with blood pressure and is localized within a major blood pressure quantitative trait locus (QTL) on rat chromosome 1 (Chr 1).^{5 6 7 8 9 10 11 12} Furthermore, cosegregation of an Sa gene polymorphism and differential Sa gene expression was demonstrated.⁷ The Sa gene therefore represents an attractive candidate to explain the effect of the Chr 1 QTL on blood pressure. Congenic experimentation recently lead to the verification of the Chr 1 blood pressure QTL spanning the Sa locus.^{13 14 15}

Despite successful QTL detection and isolation of a large congenic region around the Sa gene locus, only fine mapping of the QTL to a small chromosomal fragment will ultimately facilitate positional cloning or positional candidate gene identification. The basis of single QTL–oriented fine mapping is similar to that of Mendelian-gene fine mapping, that is, analysis of recombinants within a congenic interval previously found to account for the phenotypic variation.

The current set of experiments was aimed to evaluate whether the Sa gene explains the effect of the Chr 1 QTL on blood pressure by congenic substitution mapping approaches. Congenic strains were developed by introgressing high blood pressure QTL alleles from the stroke-prone spontaneously hypertensive rat (SHRSP) into the normotensive Wistar-Kyoto (WKY-1) reference strain. Blood pressures in congenic animals were determined by radiotelemetry at baseline and after dietary sodium loading. Our current results provide definitive evidence that the Sa gene cannot be considered a candidate within the investigated QTL on Chr 1. This would currently allow the localization of the Chr 1 blood pressure QTL centromerically to the Sa gene locus, possibly, as recently suggested,¹⁶ guiding the genetic analysis for human essential hypertension.

	Methods

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Animals
All animals were obtained from our original Heidelberg (indicated by the suscript HD) colonies of SHRSP_HD and WKY-1_HD (subsequently referred to as SHRSP and WKY-1) at the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany, and represented the same colonies that were used in our previous F₂ experimentation that lead to the identification of the blood pressure QTL on Chr 1.¹² The WKY-1 strain has been characterized elsewhere.¹⁷ Experimental procedures for animal housing and breeding have been reported previously.¹⁷ All animal experiments were conducted in accordance with institutional guidelines for the care and use of laboratory animals.

Breeding
We have previously reported on a blood pressure QTL on Chr 1 that included the Sa gene locus.¹² This locus was identified by marker D1M7Mit236 in an F₂ (WKY-1xSHRSP) intercross and was mapped to a chromosomal region flanked by markers D1 Mit2 and Mt1pa (Figure 1). The SHRSP blood pressure allele between Mt1pa and D1 Mit2 was transferred onto the WKY-1 background by 8 successive backcrosses starting from F₁ animals. This was accomplished by breeding a male SHRSP with a female WKY-1. Each subsequent backcross was performed by mating male rats that have genotypically been confirmed to be heterozygous for the SHRSP-Mt1pa/D1 Mit2 allele with female WKY-1 rats. The identification of breeder animals within each backcross generation was accomplished by analyzing multiple simple-sequence length polymorphisms (SSLP) within the region of interest, including markers exceeding the 100:1 odds support interval for the localization of the QTL on either side (Figure 1). Before homozygous animals were bred, female rats that were heterozygous for the Chr 1 QTL were mated with male WKY-1 animals. Male littermates again were mated with WKY-1 female rats, and their offspring was brotherxsister mated to produce homozygous WKY-1.SHRSP-Mt1pa/D1 Mit2 congenic animals. This breeding scheme ensured that, on average, >99.8% of the background genome that included both gender chromosomes were derived from the WKY-1 recipient. Congenic sublines were established by mating heterozygous WKY-1.SHRSP-Mt1pa/D1 Mit2 with WKY-1, the offspring was genotyped to identify recombinations with the use of SSLP markers. Appropriate animals were subsequently bred to homozygosity. This led to the establishment of the congenic subline WKY-1.SHRSP-Mt1pa/D1Rat57.

View larger version (14K): [in this window] [in a new window]   Figure 1. Schematic of rat Chr 1 and regions introgressed in the congenic strains (not drawn to scale). Numbers next to the chromosome and congenic segments indicate the genetic distance in cM. Bar to the left of Chr 1 represents the 100:1 odds interval for localization of the blood pressure QTL identified in F2 (WKY-1xSHRSP) cross. The arrow indicates the obtained maximum LOD score of 5.0 at marker D1M7Mit236.12 D1M7Mit236 denotes a mouse marker that also amplifies the homologous rat locus; terminology for loci used is in accordance with the guidelines of the committee on rat gene nomenclature.29 The black and shaded areas show the minimal and potentially maximal segments introduced into WKY-1.SHRSP-Mt1pa/D1Rat200 and WKY-1.SHRSP-Mt1pa/D1Rat57, respectively.

Blood Pressure Measurements
For all experiments a radiotelemetric method (Data Sciences International), which allows highly accurate and reproducible blood pressure determinations, was used as previously reported¹⁷ to characterize WKY-1 progenitor and congenic animals. Animals were operated under anesthesia at 12 weeks of age and were allowed to recover for 14 days. Hemodynamic measurements were performed from week 14 to week 16 after birth at baseline and during the following 12 days of dietary sodium loading (1% NaCl in drinking water with free access).

Genotype Determination
DNA was extracted according standard procedures from tail tips. SSLP were obtained from a panel we used previously^{18 19} ; additional oligonucleotide sequences for published microsatellites were obtained from public databases (http://www.genome.wi.mit.edu/rat/public or http://www.well.ox.ac.uk/~bihoreau/). PCR was performed on 50 ng of genomic DNA in a final volume of 10 µL, which contained 100 nmol/L of each primer, 200 µmol/L dNTPs, 1.5 mmol/L MgCl₂, 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 9.0 at 25°C), 0.1% Triton X-100, and 0.25 U of Taq DNA Polymerase (Promega). The forward primer was labeled with [³²P]ATP by T4 polynucleotide kinase. PCR products were processed and subsequently analyzed by autoradiography after PAGE as described.¹⁷

Statistical Analysis
Differences in blood pressure between progenitor and congenic/subcongenic strains were evaluated by ANOVA. Linkage analysis of Chr 1 and blood pressure in the F₂ (WKY-1xSHRSP) has been reported¹² and was calculated by MAPMAKER/EXP and MAPMAKER/QTL²⁰ with blood pressure values adjusted to male levels and the first reciprocal cross.¹⁸ All blood pressure values are expressed as mean±SD.

	Results

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Genetic Characterization of Chr 1 Congenic/Subcongenic Animals
The transferred segments in the original congenic strain and a congenic substrain are presented in Figure 1. Additionally, Figure 1 shows the localization of the 100:1 odds support interval of the previously published blood pressure QTL on Chr 1 spanning the Sa gene locus in the F₂ (WKY-1xSHRSP) intercross¹² for comparison.

Further genotype analysis with newly available markers for rat Chr 1 was performed in the original WKY-1.SHRSP-Mt1pa/D1 Mit2 congenic strain. The results indicated that this strain inherited a fragment derived from SHRSP that spanned at least the chromosomal segment between markers D1Rat200 and Mt1pa. Genotyping analysis in the subcongenic line confirmed the successful transfer of a subsegment from SHRSP onto the WKY-1 genetic background, which defined WKY-1.SHRSP-Mt1pa/D1Rat57 as a congenic substrain of the WKY-1.SHRSP-Mt1pa/D1Rat200 strain (Figure 1). In the WKY-1.SHRSP-Mt1pa/D1Rat57 congenic substrain, the chromosomal region centromeric from the Sa gene was substituted by WKY-1 parental alleles (Figure 1). SSLP analysis with the use of 73 genetic markers throughout the genome confirmed the congenic status of the animals designated WKY-1.SHRSP-Mt1pa/D1Rat200 and WKY-1.SHRSP-Mt1pa/D1Rat57 (data not shown).

Phenotype Characterization of Congenic Animals
Blood pressures were determined in WKY-1.SHRSP-Mt1pa/D1Rat200 and WKY-1. Systolic and diastolic blood pressure values were significantly higher in WKY-1.SHRSP-Mt1pa/D1Rat200 as compared with WKY-1 at baseline (16 weeks of age, day before NaCl loading was initiated; P<0.001 and P<0.001, respectively) and after 12 days of NaCl exposure (P<0.001 and P<0.001, respectively, Table). The strain differences in blood pressure persisted consistently over the whole time period studied (Figure 2A) and mirrored the punctual observations made at baseline and on day 12 of sodium exposure. The difference in the increase of blood pressure between the 2 strains after NaCl loading was not statistically significant.

View this table: [in this window] [in a new window]   Table 1. Blood Pressures in Parental and Congenic Rats Obtained by Radiotelemetry

View larger version (19K): [in this window] [in a new window]   Figure 2. Twenty-four-hour average mean arterial blood pressure determined by radiotelemetry over a period of 12 days before and 12 days after dietary sodium loading. Animals were operated on at 12 weeks of age and were subsequently allowed to recover for 2 weeks before blood pressure measurements were taken. Blood pressure values were averaged at each 24-hour period and represented 300 individual measurements in each rat. Subsequently group averages were calculated. A, Comparison between WKY-1.SHRSP-Mt1pa/D1Rat200 (n=9) and WKY-1 (n=11). Vertical bars indicate SD of group averages. B, Comparison between WKY-1.SHRSP-Mt1pa/D1Rat57 (n=11) and WKY-1 (n=12). For clarity, graphical representation of SDs was omitted.

Phenotype Characterization of Subcongenic Animals
Measurements of the congenic substrain WKY-1.SHRSP-Mt1pa/D1Rat57 and WKY-1 progenitors did not show a difference in either systolic or diastolic blood pressure at baseline (P=0.83 and P=0.90, respectively) or after NaCl loading (P=0.56 and P=0.89, respectively; Table). No difference in blood pressure was detected at any time point investigated (Figure 2B). There was a significant but equal increase in blood pressure in response to NaCl exposure in both WKY-1.SHRSP-Mt1pa/D1Rat57 and WKY-1, which showed no differences between strains (Figure 2B, Table).

	Discussion

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In this paper, we describe a series of studies conducted to further define our previous findings of a blood pressure relevant locus on Chr 1 that segregates among the SHRSP and WKY-1 strains. In our present studies, we combined congenic experimentation with the development of subcongenic animals, with only a fraction of the initial congenic segment for the QTL region on Chr 1, to initiate fine mapping within this region. The present investigations demonstrate that this blood pressure QTL on Chr 1 is localized centromeric to the Sa gene locus. Therefore, the Sa gene does not represent the gene that explains the observed blood pressure variation expressed by this QTL on Chr 1.

The hypothesis that this Chr 1 QTL contains a gene or genes that influence blood pressure is supported by the isolation of this QTL in congenic animals. Introgressing a large chromosomal region from SHRSP into WKY-1 animals resulted in the establishment of the congenic strain WKY-1.SHRSP-Mt1pa/D1Rat200 (Figure 1). This congenic strain encompassed a region of Chr 1 that exceeded the 100:1 odds support interval for the initial localization of this QTL in F₂ (SHRSPxWKY-1) animals and spanned the Sa gene locus. The increase in blood pressure of 10 mm Hg in WKY-1.SHRSP-Mt1pa/D1Rat200 congenic animals compared with WKY-1 progenitors is in agreement with recent reports on blood pressure effects in Chr 1 congenic strains with SHR and WKY or Brown Norway rats as model strains.^{13 14 15} A more pronounced blood pressure response after NaCl loading in congenic WKY-1.SHRSP-Mt1pa/D1Rat200 compared with WKY-1 reference animals, although theoretically expected from data obtained in the F₂ (WKY-1xSHRSP) cross,¹² was absent, which suggested a less marked phenotypic effect of this QTL on the NaCl-induced blood pressure in the absence of overall higher blood pressure attributed to many QTLs in the F₂ cohort. The overall effect of this blood pressure QTL accounted for 40% of the blood pressure variance observed after NaCl loading in the F₂ (WKY-1xSHRSP) cross.

The relevance of the Sa gene as a candidate for blood pressure variation was further investigated by initiating congenic substitution mapping approaches. Our study was designed to differentiate between blood pressure effects of the Sa gene locus and the genetic marker D1M7Mit236, which gave rise to the maximal LOD score in our F₂ (SHRSPxWKY-1) cohort (Figure 1) detecting the QTL. We identified a recombinant congenic substrain that carried SHRSP alleles defined by markers Mt1pa and D1Rat57 and exhibited wild-type alleles centromeric from marker D1Rat57 (Figure 1). The fact that there was no detectable blood pressure effect in the congenic substrain WKY-1.SHRSP-Mt1pa/D1Rat57 compared with the WKY-1 progenitor strain rules out the Sa gene as a positional candidate for hypertension. Therefore, the QTL is localized centromeric with reference to the Sa gene locus (Figure 1), possibly between markers D1Rat57 and marker D1 Mit2 although the centromeric confines of the transferred SHRSP alleles are likely to exceed the latter. These data are in agreement with the maximum placement of this QTL in our F₂ (WKY-1xSHRSP) intercross that is 3.8 cM centromeric to the Sa gene locus (Figure 1) at marker D1M7Mit236.

Our data rule out 2 additional genes, the ß- and -subunits of the epithelial sodium channel (Scnn1b and Scnn1g, respectively) as positional candidates that represent this Chr 1 QTL. Mutations in these genes have been identified in patients with Liddle's syndrome, which leads to the formation of constitutively activated epithelial sodium channels thus increasing renal sodium reabsorption and causing hypertension.^{21 22}

Moreover, Scnn1b and Scnn1g have recently been implicated in possibly playing a role as basic mechanotransducers in baroreceptor nerve terminals.²³ Both genes were previously shown to be closely linked to the Sa gene locus, just on the border of the 100:1 odds support interval of this blood pressure QTL (Figure 1).¹² Although earlier investigations could not reveal any relevant coding sequence mutations in different models of genetic hypertension, more subtle mutations, eg, in regulatory elements, could not be excluded in these studies.¹² The choice to use WKY-1 as the recipient strain for constructing Chr 1 congenic lines stems from our observation that the Chr 1 QTL exhibits a significant blood pressure effect only in F₂ (WKY-1xSHRSP) animals¹² but not in the F₂ (WKYxSHRSP) cohort²⁴ according to stringent statistical criteria.²⁵

The Chr 1 blood pressure QTL has been confined to a region centromeric of the Sa gene locus. In contrast to the adjacent region telomeric of the Sa gene (11p15.5), this region is syntenic to human chromosome 11p15.4-p15.3, which has not previously been investigated in human hypertension. This provides a possible explanation why the findings on rat Chr 1 could only partly be corroborated in human hypertension thus leading to conflicting results.^{26 27 28 30 31}

The present data warrant a note of caution on potential pitfalls of focusing on candidate genes at early stages in the analysis of complex disease phenotypes. Although the Sa gene exemplifies a prime candidate gene because of its cosegregation with the disease phenotype, expression in the kidney, and differential expression pattern between hypertensive and normotensive parental strains, it should be observed as a marker in linkage studies. Only after a more rigorous approach, such as congenic experimentation and confinement to a small chromosomal region, can a candidate gene be viewed seriously as a bona fide candidate gene.

Given the marked consistency of the effect of this Chr 1 QTL on blood pressure variation of 10 mm Hg within our and several other congenic strains,^{13 14 15} it should be emphasized that results from congenic experimentation with the use of different parental strains might be integrated. If indeed the same QTL alleles are operative in different strains, this would significantly advance the fine mapping of the QTL locus by comparing blood pressure effects and genetic breakpoints within several congenic/subcongenic strains.

Despite major successes in QTL detection, fine mapping has been difficult to achieve. This difficulty is presently a major obstacle to both positional cloning and positional candidate gene identification. Further work on the establishment of additional congenic lines that carry smaller subfractions of the Chr 1 blood pressure QTL defined in this study will facilitate both goals.

	Acknowledgments

 
We are grateful to Marion Somnitz and Ralph Plehm for assistance with telemetric blood pressure measurements, Susanne Weidner and Dr Lutz Dietzel for assistance with animal breeding, and Heidemarie Müller and Gabriele Siebert for further technical help. This work was supported in part by the Deutsche Forschungsgemeinschaft (to D.G., Ga175/8-2) and by the EURHYPGEN II Concerted Action within the BIOMED program of the European Community.

Received March 1, 1999; first decision April 1, 1999; accepted June 9, 1999.

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