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(Hypertension. 1996;28:1118-1122.)
© 1996 American Heart Association, Inc.

Articles

Analysis of Quantitative Trait Loci for Blood Pressure on Rat Chromosomes 2 and 13

Age-Related Differences in Effect

Nilesh J. Samani; Dominique Gauguier; Madeleine Vincent; Michael A. Kaiser; Marie-Therese Bihoreau; David Lodwick; Robert Wallis; Valerie Parent; Phillip Kimber; Fraser Rattray; John R. Thompson; Jean Sassard; Mark Lathrop

the Departments of Medicine (N.J.S., M.A.K., D.L., P.K.), Cardiology (N.J.S., M.A.K., F.R.), and Ophthalmology (J.R.T.), University of Leicester (UK); Wellcome Trust Center for Human Genetics, Oxford, UK (D.G., M.-T.B., R.W., V.P., M.L.); and URA CNRS 1483, Faculty of Pharmacy, Lyon, France (M.V., J.S.).

	Abstract

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Previous studies have suggested the presence of quantitative trait loci (QTLs) influencing blood pressure on rat chromosomes 2 and 13. In this study, we mapped the QTLs in F₂ rats derived from a cross of the spontaneously hypertensive rat and the Wistar-Kyoto rat and analyzed the effect of the QTLs on blood pressures measured longitudinally between 12 and 25 weeks of age. We analyzed 16 polymorphic markers spanning 147.3 cM on chromosome 2 and 13 markers spanning 91.6 cM on chromosome 13. Both chromosomes contained QTLs with highly significant effects on blood pressure (peak logarithm of the odds [LOD] scores, 5.64 and 5.75, respectively). On chromosome 2, the peak was localized to a position at anonymous marker D2Wox7, 2.9 cM away from the gene for the sodium-potassium ATPase ₁-subunit. On chromosome 13, the major peak coincided with the marker D13Mit2, 21.7 cM away from the renin gene, but there was a suggestion of multiple peaks. The effect of the QTL on chromosome 2 was seen throughout from 12 to 25 weeks of age, whereas interestingly, the effect for the QTL on chromosome 13 was maximal at 20 weeks of age but disappeared at 25 weeks of age, presumably because of the effect of either epistatic factors or environmental influences. The findings provide important information on QTLs influencing blood pressure on rat chromosomes 2 and 13 that will be useful in localizing and identifying the causative genes and emphasize the importance of age being taken into account when the effects of individual QTLs on a trait that shows significant age-related changes are being analyzed.

Key Words: genetics • rats, inbred SHR • renin • Na⁺,K⁺-exchanging ATPase

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Cosegregation analysis with DNA markers has provided a powerful tool for identification of genetic loci influencing blood pressure (BP) in genetic models of hypertension. Initial studies used polymorphisms in candidate genes to investigate specific loci.^{1 2 3 4 5 6 7} However, these studies by themselves do not identify the causative gene and only point to a chromosomal region that is genetically linked with BP. More recently, the availability of a rat genetic linkage map⁸ has made it possible to more accurately define boundaries containing the quantitative trait locus (QTL) at individual sites, an important step in identifying the causative gene. QTLs influencing BP have been mapped to varying degrees of precision on rat chromosomes 1, 2, 4, 5, 10, 17, 18, 19, and X.^{9 10 11 12 13 14 15} In this article, we report our analysis of QTLs on rat chromosomes 2 and 13 in second filial generation (F₂) rats derived from a cross of the spontaneously hypertensive rat (SHR) and the Wistar-Kyoto rat (WKY).

	Methods

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Animal Procedures
The generation and characterization of the F₂ rats used in this study have been described in detail previously.^{16 17} Briefly, 6 SHR and 6 WKY (3 males and 3 females of each), derived from the breeding stock of Charles River Laboratories (Margate, Kent, UK), were mated to obtain F₁ hybrids. F₁ rats (16 males and 16 females) were randomly mated to generate 233 male F₂ rats. Rats were housed under controlled conditions (temperature, 21±1°C; humidity, 60±10%; 12-hour day/night cycle), were fed standard rat chow (Rat & Mouse No. 3 Breeding Diet, Special Diet Services Ltd) containing 0.25% sodium and 0.66% potassium, and were given free access to tap water.

Indirect BP was measured at 12, 16, and 20 weeks of age in conscious rats by tail plethysmography (Narco BioSystems physiograph and transducer). Rats were prewarmed to 34°C for 20 minutes before measurements were taken between 9 AM and 1 PM. At each age, readings were taken on 2 separate days, with three measurements on each occasion. The average of all readings was taken as the value for that age. In addition, 193 F₂ rats underwent direct BP measurements at 25/26 weeks of age. This was carried out in conscious, unrestrained rats as described by Su et al.¹⁸ Briefly, with rats under halothane anesthesia (2% in oxygen), a polyethylene catheter (PE-10, 0.28-mm ID) was inserted via the femoral artery into the lower abdominal aorta, tunneled subcutaneously, and exteriorized at the neck. Rats were allowed to recover for at least 24 hours with food and water ad libitum. The arterial catheter was then connected to a BP transducer (Statham P23 ID, Gould Inc) via a rotating swivel that allowed the rats to move freely. After calibration was verified, systolic and diastolic BPs and heart rate were recorded beat by beat for 2 consecutive hours between 10 AM and 5 PM. The data were processed off-line following the method of Gustin et al,¹⁹ and mean values were calculated from the full recording period.

All procedures were carried out in accordance with our institutional guidelines.

Genotype Determinations
Markers on chromosomes 2 and 13 that could be analyzed by polymerase chain reaction (PCR) amplification were identified from published maps^{8 12 20} and from the panel of rat microsatellite markers developed by the Wellcome Trust Centre for Human Genetics, Oxford, UK (data available on ftp://ftp.well.ox.ac.uk/pub/genetics/ratmap) and were tested for polymorphism between our SHR and WKY DNAs. F₂ rats were then genotyped for those found to be polymorphic. PCR was performed with microtiter plates as previously described.²¹ The reaction volume was 20 µL containing 45 mmol/L Tris (pH 8.8), 11 mmol/L (NH4)₂SO₄ (pH 8.8), 1 mmol/L MgCl₂, 6.7 mmol/L ß-mercaptoethanol, 4.5 µmol/L EDTA, 25 µmol/L dNTPs, 50 ng genomic DNA, 0.25 µmol/L of each primer, and 0.4 U Taq polymerase (Perkin-Elmer). The PCR program consisted of an initial 4 minutes at 96°C followed by 35 cycles of 30 seconds at 94°C, 45 seconds at 55° or 60°C, and 10 seconds at 72°C. PCR products were separated by electrophoresis on 8% polyacrylamide sequencing gels and transferred onto nylon membranes (PALL). For each marker, the membranes were then hybridized with one of the primers radioactively labeled with [-³²P]dCTP by terminal transferase (Boehringer). After washing, the filters were exposed to autoradiography film (X-OMAT AR, Eastman Kodak) for 2 to 14 hours at -80°C.

Linkage and Statistical Analysis
Linkage maps and QTL localization were done with the MAPMAKER programs^{22 23} kindly provided by Dr Eric Lander (Whitehead Institute, Cambridge, Mass). Cosegregation of BP with genotypes at a marker locus was evaluated by ANOVA with the use of MINITAB (release 7) (Minitab Inc).

	Results

Top Abstract Introduction Methods Results Discussion References

 
We analyzed 16 polymorphic markers spanning 147.3 cM on chromosome 2 (Table 1) and 13 markers spanning 91.6 cM on chromosome 13 (Table 2). Both chromosomes contained QTLs with highly significant effects on BP (peak logarithm of the odds [LOD] scores, 5.64 and 5.75, respectively) (Figs 1 and 2). The effect of the QTL on chromosome 2 was seen throughout from 12 to 25 weeks of age (Fig 1), whereas interestingly, the effect for the QTL on chromosome 13 was maximal at 20 weeks of age but largely disappeared at 25 weeks of age (Fig 2).

View this table: [in this window] [in a new window]   Table 1. Markers Analyzed on Chromosome 2

View this table: [in this window] [in a new window]   Table 2. Markers Analyzed on Chromosome 13

View larger version (12K): [in this window] [in a new window]   Figure 1. Quantitative trait locus logarithm of the odds (LOD) plots for markers on chromosome 2 and blood pressures at different ages. See Table 1 for list of markers. Horizontal dotted line indicates the threshold for significance of the LOD score (3.0). bp12 indicates blood pressure at 12 weeks; bp16, at 16 weeks; bp20, at 20 weeks; sbp25, systolic blood pressure at 25 weeks; dbp25, diastolic blood pressure at 25 weeks; At1br, angiotensin II subtype 1b receptor; Cpb, carboxypeptidase B; Gca, guanylyl cyclase A receptor; and Atp1a1, Na+,K+-ATPase 1.

View larger version (11K): [in this window] [in a new window]   Figure 2. Quantitative trait locus logarithm of the odds (LOD) plots for markers on chromosome 13 and blood pressures at different ages. See Table 2 for list of markers. Horizontal dotted line indicates the threshold for significance of the LOD score (3.0). Abbreviations as in Fig 1 legend, and Atp1a2 indicates Na+,K+-ATPase 2.

On chromosome 2, the peak was localized to a position at anonymous marker D2Wox7, 2.9 cM away from the gene for the Na⁺,K⁺-ATPase ₁-subunit (Fig 1). On chromosome 13, the major peak coincided with the marker D13Mit2, 21.7 cM away from the renin gene, but there was a suggestion of multiple peaks (Fig 2). At 20 weeks, the loci on chromosomes 2 and 13 accounted for 13.7% and 11.8% of the total variance in BP, respectively.

To further illustrate the differing age effects of the QTLs on the two chromosomes and to allow comparison with previous reports,^{1 2 3 12} Table 3 shows BPs by genotype at the different ages for the Na⁺,K⁺-ATPase ₁ locus on chromosome 2 and the renin locus on chromosome 13. The effect of the QTL on chromosome 2 appears to be recessive, and the effect of the QTL on chromosome 13 appears to be codominant.

View this table: [in this window] [in a new window]   Table 3. Blood Pressure by Genotype at Different Ages for Na+,K+-ATPase 1 Locus (Chromosome 2) and Renin Locus (Chromosome 13)

	Discussion

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In this study, we provide strong evidence for the presence of QTLs influencing BP on rat chromosomes 2 and 13 and map their location. We focused on these chromosomes because of previous data in other crosses reporting QTLs^{12 24} or positive cosegregation with individual markers.^{1 2 25}

Our data for chromosome 2 agree with the findings of Deng et al¹² in crosses involving the Dahl salt-sensitive rat. Like them, we found the peak location for the QTL to be near the Na⁺,K⁺-ATPase ₁ gene and some distance away from another candidate gene, guanylyl cyclase A/atrial natriuretic peptide receptor A (Gca),²⁶ where the LOD score was more than 1.5 LOD lower (Fig 1). With a cutoff of ±1 LOD, our data suggest that the most likely location of the QTL is in an approximately 15-cM interval flanked by markers D2Wox23 and D2Mgh12. This information should be useful for the construction of congenic lines for narrowing down the QTL.

Previous studies have suggested the presence of a second QTL on chromosome 2 affecting BP located near the angiotensin II subtype 1b receptor (At1br)/carboxypeptidase (Cpb) locus.^{24 27} In a cross of Lyon hypertensive and normotensive rats, the locus was found to particularly affect pulse pressure measured at 30 weeks.²⁷ In our study, we measured direct BP using the same technique as that in the study by Dubay et al,²⁷ but we found no evidence for a QTL near the At1br/Cpb locus affecting either pulse pressure (data not shown) or other BP phenotypes (Fig 1).

Previous studies on chromosome 13 have focused only on the renin gene and given conflicting results.^{1 2 3} In a cross of Dahl salt-sensitive and salt-resistant rats,¹ the renin allele from the hypertensive strain cosegregated with an increase in BP, as in our case. However, more recently in congenic lines, St Lezin et al²⁸ found that transfer of an approximately 10-cM fragment of the Dahl salt-sensitive chromosome 13 containing the renin gene into the Dahl salt-resistant rat somewhat paradoxically resulted in a lower rather than higher BP. Our study shows that the chromosome 13 QTL raising BP could be located some distance from the renin gene (Fig 2), which could provide an explanation for the finding of St Lezin et al,²⁸ although it needs to be emphasized that with a peak LOD score of 4.8 at the renin locus, our data certainly cannot exclude the possibility of an effect of the renin gene. Indeed, with a region of approximately 50 cM with a LOD score greater than 3.0 for BP at 20 weeks, our results are most consistent with the presence of more than one QTL influencing BP on chromosome 13. Development of congenic lines with different segments of the SHR chromosome 13 between D13kyo3 and D13Mit3, the markers flanking the region of interest, should help in defining the number and characteristics of QTLs influencing BP on chromosome 13.

Much interest has focused on environmental factors such as salt that may modify the effect of a BP QTL.^{9 10} Less attention has been paid to the temporal relationships of QTLs. Given that BP is an age-dependent phenotype and that different QTLs are likely to act through different mechanisms that may themselves show age dependency, temporal variations in the effects of QTLs would not be surprising. The design of our experiment allowed us to test this to some extent, and our findings on the QTLs on chromosomes 2 and 13 provide support for this paradigm. The findings for the two QTLs also contrast with the temporal pattern we previously observed for the QTL at the S_A locus on chromosome 1 in our cross, in which the effect was apparent only at 20 weeks of age and maximal at 25 weeks.¹⁶ The most surprising finding was the marked diminution of the effect of the QTL(s) on chromosome 13 between 20 and 25 weeks of age. The findings cannot be due to genotyping error, as we used the same genotypes to analyze data at all ages. Since we measured BP at 20 weeks indirectly in conscious but restrained rats and that at 25 weeks directly in freely moving rats, it is possible that the difference reflects the mode of BP measurement and particularly the effect of stress, which is likely to have been greater with restraint; ie, the QTL on chromosome 13 specifically influences the BP response to stress. Our study cannot exclude this possibility, but even if this is the case, it contrasts with the effect of the QTL on chromosome 2. The alternative possibility is that the decline in magnitude of the effect of the chromosome 13 QTL reflects an interaction with epistatic genetic factors. Such interactions have already been reported in relation to other loci.^{25 29} We have analyzed for an interaction between the QTL on chromosome 13 and those on chromosomes 2 and 1¹⁶ and have not found any effect (data not shown). However, epistatic factors need not themselves have an independent effect on BP,²⁹ and the identification of such factors in our cross will require a more comprehensive genome scan. In the meantime, our data emphasize the importance of age being taken into account when the effects of individual QTLs on a trait that shows significant age-related changes are being analyzed.

In summary, in a cross of the SHR and WKY, we have mapped QTLs on rat chromosomes 2 and 13 that influence BP. The data will be helpful in further localizing and ultimately identifying the causative genes on the two chromosomes.

	Acknowledgments

 
These studies were funded by the Wellcome Trust, the British Heart Foundation, and the EURHYPGEN Concerted Action of the CEC. We are grateful to Dr Eric Lander for supplying the MAPMAKER programs.

	Footnotes

 
Reprint requests to Dr N.J. Samani, Department of Cardiology, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Groby Rd, Leicester LE3 9QP, UK.

Received June 19, 1996; first decision July 11, 1996; accepted August 9, 1996.

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