Human Molecular Genetics

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Human Molecular Genetics, 2003, Vol. 12, No. 4 435-439
© 2003 Oxford University Press

Interaction between blood pressure quantitative trait loci in rats in which trait variation at chromosome 1 is conditional upon a specific allele at chromosome 10

Jan Monti^1,2, Ralph Plehm¹, Herbert Schulz^1,3, Detlev Ganten^1,3, Reinhold Kreutz³ and Norbert Hübner^1,3,*

¹Max-Delbrück-Center for Molecular Medicine (MDC), Berlin-Buch, Germany, ²Franz-Volhard-Clinic, HELIOS-Klinikum, Charite, Humboldt-University Berlin, Germany and ³Department of Clinical Pharmacology, Freie University Berlin, Germany

Received November 18, 2002; Accepted December 17, 2002

	ABSTRACT

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We have used inbred and congenic rat strains in F₂ segregation studies to discover epistasis in a polygenic model of hypertension. Previously, we have found evidence that the presence of a blood pressure quantitative trait locus (QTL) on chromosome 1 is conditional upon the allele status of chromosome 10. To prove the existence of an epistatic interaction we have analyzed congenic strains for chromosome 1 and 10 carrying high blood pressure QTL alleles from the spontaneously hypertensive rat on a normotensive background of the Wistar–Kyoto (WKY) rat. Additionally, a double congenic strain was developed with both chromosome 1 and 10 high blood pressure QTL alleles on the WKY background. Analysis of variance for blood pressure phenotypes as determined by radiotelemetry showed a significant effect for chromosome 10 but not chromosome 1 QTL alleles and demonstrated a significant interaction between the two loci (P<0.05). The interaction accounted for 5 mmHg of blood pressure. Thus, the identification of epistasis is critical to the understanding of the quantitative nature of blood pressure genetics.

	INTRODUCTION

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Human primary hypertension is one of the most common chronic diseases (1,2). It shows a significant degree of heritability and is commonly recognized as a complex, polygenic disorder, with the exception of rare monogenetic forms (3). The identification of genes regulating blood pressure that may lead to elevated blood pressure is difficult due to the complex nature of this trait. The genetic analysis of blood pressure control in many aspects is paradigmatic for polygenic quantitative trait analysis. Polygenic quantitative traits result from interactions between multiple genes and the environment. Moreover, it is obvious that epistatic interactions between or among quantitative trait loci (QTLs) are possible if not likely (4,5). Identification of these interactions becomes crucial to elucidate pathophysiological pathways involved in the development and maintenance of hypertension.

We have searched for epistatic effects between QTL that produce a substantial amount of trait variation. In previous linkage analysis of an F₂ population, we have identified a major blood pressure QTL on rat chromosome 10 (6,7). Using congenic approaches, we subsequently demonstrated that this locus (spanning more than 35 cM) does in fact contain two separate loci that segregate independently and confer differential phenotype characteristics, i.e. basal and salt-loaded blood pressure (8). Further, we have used chromosome (Chr) 10 congenic rats (W.S.10) to perform a second F₂ [spontaneously hypertensive rats (SHRSP)xW.S.10] cosegregation study and identified a new blood pressure QTL region on rat chromosome 1 for salt-loaded systolic blood pressure (9). These data suggested an interdependence of the two blood pressure QTLs (Table 1). In the present work we analyzed double congenic, single congenic and parental strains and found a significant epistatic interaction on systolic blood pressure of the QTL on Chr 1 and 10. The variation attributed to the blood pressure effect of the Chr 1 QTL was conditional upon the presence of the particular allele on chromosome 10.

View this table: [in this window] [in a new window]   Table 1. Summary of linkage results in F2 populations, Previously, linkage to blood pressure was detected in an F2 (SHRSPxWKY intercross), which encompassed n=115 animals (LOD score 5.1) (6,7). By fixing the SS genotype on chromosome 10 in an otherwise segregating F2 (SHRSPxW.S.10) population, n=139, a blood pressure QTL on rat chromosome 1 was detected (LOD score 5.0) (8,9). This QTL was not present in an F2 (SHRSPxWKY) population, suggesting that the expression of the Chr 1 QTL is conditional upon the presence of S alleles at Chr 10

 
Our results demonstrate the feasibility of combining the use of congenic strains in linkage analysis for the discovery and classical congenic experimentation for the proof of epistatic interactions of quantitative genetic factors regulating physiological systems like blood pressure control. Information about genetic factors identified in experimental systems may provide new insights into disease mechanisms that can then be applied to the generation and testing of hypotheses regarding the pathogenesis of the disease in humans.

	RESULTS

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All three congenic strains are essentially Wistar–Kyoto (WKY) rats except that for the blood pressure QTL on Chr 1 and Chr 10 they carry high blood pressure alleles substituted for the low blood pressure WW genotype (W.S.1 and W.S.10, respectively); see Figure 1 for details. The Chr 1/10 double congenic line (W.S.1/10) carries both high blood pressure QTL regions. Table 2 shows the telemetric data for systolic blood pressure for WKY, W.S.1, W.S.10 and double congenic W.S.1/10 rats after 1% sodium loading. The 2x2 factorial ANOVA immediately reveals the statistical interaction between Chr 1 and Chr 10 on systolic blood pressure. A more intuitive interpretation is given in Figure 2.

View larger version (19K): [in this window] [in a new window]   Figure 1. Genetic maps of the regions represented in congenic strains. Distances are given in centiMorgans. The black bars to the right of each map represent the segments introgressed into the WKY strain. Open bars on the ends of these segments mark the region in which recombination occurred. Both segments were derived from the SHRSP strain (donating alleles designated S). W denotes alleles from the recipient WKY strain.

 

View this table: [in this window] [in a new window]   Table 2. Values for diastolic and systolic blood pressure after NaCl loading; 2x2 factorial ANOVA tested for main effects of Chr1 and Chr10 genotype and for interaction between the two. One-way ANOVA tested for differences between congenics and WKY rats

 

View larger version (12K): [in this window] [in a new window]   Figure 2. Schematic representation of epistatic interaction between Chr 1 and 10. Effect of genotype combinations on systolic blood pressure after sodium loading. W refers to WKY alleles, S to SHRSP alleles in the congenic regions shown in Figure 1. The increments labeled a and b represent single locus effects on blood pressure, and the increment labeled interactive effects represents the trait variation at Chr 1, which is conditional upon the allele status of Chr 10. The dotted line represents the anticipated blood pressure effects if both loci were purely additive, i.e. absence of epistatic interaction between the two loci.

 
Changing the blood pressure QTL on Chr 1 in the inbred WKY animals from the low WW genotype to the high SS genotype is represented by the Chr 1 congenic W.S.1 (Fig. 2). Such substitution increased the blood pressure from 126.1±0.5 to 128.6±1.2 mmHg, labeled as a in Figure 2, which was not significant. Changing the blood pressure QTL on Chr 10 in inbred WKY from the low WW genotype to the high SS genotype is represented by the Chr 10 congenic (Figure 2). Such substitution increased the blood pressure significantly from 126.1±0.5 to 129.4±0.8 mmHg, or 3.3 mmHg, labeled as b in Figure 2. On the assumption that the QTL alleles on Chr 1 and Chr 10 were additive, the expected increase in blood pressure upon changing from low to high blood pressure alleles on both chromosome 1 and 10 would be the increment labeled a+b in Figure 1, or 5.8 mmHg. The actual effect is to increase blood pressure from 126 to 137 mmHg in the WKY strain, an increase of 11 mmHg. The increment above the 5.8 mmHg expected, i.e. 11-5.8 or 5.2 mmHg, represents the component due to the interaction between Chr 1 and Chr 10 on the WKY genetic background (labeled interactive effect in Fig. 1). The epistatic interaction was corroborated under basal conditions (interactive effect 4.8 mmHg, P<0.05; data not shown).

	DISCUSSION

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In this report we describe a series of studies conducted to detect epistatic interactions between blood pressure QTLs. We combined the methods of interval mapping with congenic experimentation. The present investigations demonstrate that trait variation on chromosome 1 is conditional upon a specific allele at chromosome 10, contributing to elevated blood pressure levels in rats. Originally we performed two independent F₂ cosegregation studies to study the genetics of blood pressure regulation. The first F₂ population was derived from a cross of SHRSP with WKY rats (6,7). In the second F₂ population we used Chr 10 congenic rats as parental progenitors instead of inbred WKY, and performed linkage and cosegregation analysis (8,9). Fixing the SS genotype in the segregating F₂ (SHRSPxW.S.10) population (Table 1) led to the identification of a blood pressure QTL on rat chromosome 1 [LOD 5.0 (9); Table 1]. This QTL was not detectable in the F₂ (SHRSP x WKY) population (6,7), thus suggesting that the QTL detection on chromosome 1 was conditional upon the high blood pressure QTL alleles on chromosome 10. Since the original F₂ (SHRSPxWKY) population was too small in size [n=115; (6,7)], it was not possible to assess with appropriate statistical power a genetic interaction between the two loci in the F₂ (SHRSPxWKY) population. Therefore, we have relied on additional congenic approaches including the construction of a double congenic strain to prove an epistatic interaction between the two blood pressure regulating loci on rat Chr 1 and 10. Our results obtained by analyzing individual and double congenic strains are consistent with the results obtained by linkage analysis. In both in congenic strains and linkage analysis, a modulating effect of the Chr 1 QTL on salt-loaded blood pressure was only present when SS alleles were fixed on Chr 10.

Several groups have identified a blood pressure QTL on rat Chr 1 in different strains in the same region as presented in this paper (Fig. 1). This might not only be due to different sets of genes contributing to blood pressure control in different (although sometimes related) inbred strains, but might be due to the lack of the appropriate genetic constellation necessary to express a specific QTL. A ‘dormant’ disease gene could contribute to the phenotypic trait depending on epistatic interactions to take place.

Our findings described in this paper are substantiated when we compare our F₂ cosegregation studies with data generated by other groups. Linkage analysis in an F₂ population, using SHR_Leicester and WKY_Leicester animals which represent different sub-lines from those that were used in our study, led to the identification of the same blood pressure QTL interval on Chr 1 in the spontaneously hypertensive rat (10). Subsequent genetic analysis of the WKY_Leicester strain revealed that WKY_Leicester rats carry identical alleles to our SHRSP strain within the Chr 10 QTL region, as defined by microsatellite marker analysis (N.Samani, personal communication). Thus, the genotype on chromosome 10 within the region discussed is critical for the phenotypic expression of the blood pressure QTL on rat Chr 1.

The genetic interaction between Chr 1 and Chr 10 on blood pressure certainly means that the genes involved code for molecules involved in blood pressure regulatory pathways that interact at some level either directly or indirectly. With this in mind, the discovery of blood pressure-regulating genes in one or the other of the interacting QTL might aid in uncovering the remaining QTL.

We found an interaction between Chr 1 and Chr 10 only for systolic blood pressure, not for diastolic blood pressure. Failure to find an epistatic interaction for diastolic blood pressure is not necessarily inconsistent, but may merely underscores differences in systolic and diastolic blood pressure regulation. Linkage to systolic without detecting linkage for diastolic blood pressure or vice versa has previously been reported in human populations and experimental rat models, demonstrating that different genetic factors contribute to systolic and diastolic blood pressure regulation (11–13).

Our findings are, in many ways, paradigmatic for the complexity of polygenic and multifactorial traits. The two loci on Chr 1 and Chr 10 modulate a remote phenotype, blood pressure, by affecting subtly sub-phenotypes (NaCl loaded blood pressure). The epistatic interaction involves an ecogenetic component, namely the response to dietary sodium intake (14), a phenomenon which is also a hallmark characteristic in many patients suffering from essential hypertension (15). Moreover the results of the present experiments emphasize the tremendous importance of high-fidelity phenotypic characterization in the analysis of remote composite phenotypes.

The importance of epistatic interactions for polygenic quantitative traits has recently been emphasized and will represent a major challenge in the genetic dissection of complex genetic traits (5,16–18). One way to systematically and more fully account for quantitative phenotypic variation due to epistasis in experimental model organisms in the future may be the availability and use of chromosome substitution strains (19,20). The analysis of genetic interactions for physiologically relevant traits like blood pressure control in model organisms may help to direct focus in the analysis of human populations for which it will be inherently more difficult to detect epistasis (18).

	MATERIALS AND METHODS

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Animals
Inbred stroke-prone SHRSP were from our colony at the Max-Delbrück-Center for Molecular Medicine, Berlin-Buch. Congenic strains previously described by us were also used (8,21). In both cases, a segment of chromosome containing a high blood pressure QTL allele from SHRSP (donor) defined the Chr 1 and Chr 10 congenic lines W.S.1 and W.S.10 respectively, on WKY background (recipient); Figure 1. The Chr 10 congenic strain was originally named WKY-1 (8), but will be referred to as W.S.10 for clarity. We constructed a double congenic, i.e. a single strain in which both the Chr 1 and Chr 10 regions were on the WKY genetic background, as follows. The Chr 10 congenic line and SHRSP were crossed and this F₁ was repeatedly back-crossed to the Chr 10 congenic W.S.10 for more than 10 generations before they were bred homozygous at the Chr 1 locus. Single Chr 1 congenic were derived by breeding W.S.1/10 to WKY rats. The resulting F₁ generation was backcrossed to WKY and offspring heterozygous WS at the Chr 1 locus and homozygous WW at Chr 10 was selected and intercrossed to derive SS offspring at Chr 1 while preserving the WW genotype at Chr 10. All congenic strains are maintained by brother–sister maiting. A genome scan with 72 polymorphic microsatellite markers outside the chromosome 1 congenic interval was carried out to confirm the status of the recipient background in the Chr 1 congenic strain W.S.1. Three to four markers were genotyped on all autosomes spaced 20–30 cM apart. All markers confirmed the WW genotype.

Genotyping
DNA was extracted according to standard protocols from tail tip biopsies. All genetic markers were based on amplification by polymerase chain reaction of polymorphic microsatellites as reported previously (8,21). Oligonucleotide primer pairs for genetic markers and genotyping protocols were given previously (8,21) or can be found at www.rgd.edu.

Phenotyping—blood pressure measurements
A radiotelemetry method, which allows highly accurate and reproducible blood pressure determinations, was used to characterize all animals investigated essentially as reported (21). Briefly, radiotelemetric pressure transducers were implanted in the abdominal cavity of the rat, with the transducer-connected capillary tubing anchored in the lumen of the abdominal aorta. Animals were allowed to recover for 14 days. Hemodynamic measurements were performed from weeks 14 to 16 after birth at baseline and during the following 12 days of dietary sodium loading (1% NaCl in drinking water with free access). This protocol mirrored the experimental procedures that were used for phenotyping of the F₂ populations that led to the initial Chr 1 and Chr 10 QTL detection.

Four groups WKY, W.S.1, W.S.10, and W.S.1/10 were evaluated for their blood pressure. At least 10–12 animals were measured in each group. If previous data was available for any of the groups they were incorporated in the analysis. This was the case for W.S.10 congenic and WKY parental animals since they were used as reference strains in the generation of Chr 1 and 10 double congenic and Chr 1 congenic strains (see above). Therefore, telemetric blood pressure measurements of 75 animals were available for analysis (n=20 WKY; n=12 W.S.1; n=33 W.S.10; n=10 W.S.1/10).

Statistical analysis
The experimental design was analyzed as a 2x2 factorial ANOVA providing an evaluation of main effects and the interaction between the genotypes on Chr 1 and 10. The main effects were (i) genotype of the congenic region on Chr 1 and (ii) genotype of the congenic region on Chr 10 either WW or SS for each locus, respectively. The data were also analyzed as a one-way ANOVA followed by contrasts among the strains using the Fisher-PLSD test. All data are expressed as means±SEM.

	ACKNOWLEDGEMENTS

 
We are grateful to Marion Somnitz for technical assistance with telemetric blood pressure measurements. This work was supported in part by a grant-in-aid from the Deutsche Forschungsgemeinschaft (DFG) and the EURHYPGEN concerted action of the European Union.

	FOOTNOTES

 
^* To whom correspondence should be addressed at: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13092 Berlin, Germany. Tel: +49 3094062530; Fax: +49 3094062110; Email: nhuebner{at}mdc-berlin.de

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