(Hypertension. 1997;30:854-858.)
© 1997 American Heart Association, Inc.
Articles |
Genetic Isolation of a Chromosome 1 Region Affecting Blood Pressure in the Spontaneously Hypertensive Rat
From the Department of Laboratory Medicine (E. St. L., W.L., J.-M.W., N.W.) and the Animal Care Facility (D.L.), University of California, San Francisco; the Institute of Biology, 1st Medical Faculty, Charles University (V.K., D.K., M.P.), and the Institute of Physiology, Czech Academy of Sciences (V.K., A.M., M.Z., V.Z., M.P.), Prague, Czech Republic.
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Abstract |
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Abstract Recent linkage studies in the spontaneously hypertensive rat (SHR) suggest that a blood pressure regulatory gene or genes may be located on rat chromosome 1q. To investigate this possibility, we replaced a region of chromosome 1 in the SHR (defined by the markers D1Mit3 and Igf2) with the corresponding chromosome segment from the normotensive Brown-Norway (BN) strain. In male SHR congenic rats carrying the transferred BN chromosome segment, 24-hour average systolic and diastolic blood pressures were significantly lower than in male progenitor SHR. Polymerase chain reaction genotyping using 60 polymorphic microsatellite markers dispersed throughout the genome confirmed the congenic status of the new strain designated SHR.BN-D1Mit3/Igf2. These findings provide direct evidence that a blood pressure regulatory gene exists on the differential segment of chromosome 1 that is sufficient to decrease blood pressure in the SHR. The SHR.BN-D1Mit3/Igf2 congenic strain represents an important new model for fine mapping and characterization of genes on chromosome 1 involved in the pathogenesis of spontaneous hypertension.
Key Words: hypertension, genetic • congenic strain • trait locus • genes
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The spontaneously hypertensive rat is the most widely used animal model of human essential hypertension and has been studied extensively using physiological and biochemical approaches.1 Despite this intensive research effort, little is known about the primary genetic lesions responsible for the defective regulation of BP in the SHR. Recent linkage studies in segregating populations suggest that a BP QTL may exist on chromosome 1 in the vicinity of the Sa gene and the genes encoding the ß and
subunits of the epithelial sodium channel
(Scnn1b and Scnn1g).2 3 4 5 6 7 Molecular
analysis of these candidate genes in the SHR so far has been
inconclusive.7 8 Moreover, the cosegregation of BP with
Sa and Scnn1b/Scnn1g may reflect the effect of a
gene linked at some distance to these genes on chromosome 1 rather than
to the genes themselves. Therefore, despite linkage studies showing a
BP QTL in the region of the Sa and Scnn1b genes,
the identification and physical location of a BP QTL on rat chromosome
1 is far from certain. In contrast to studies in segregating populations, chromosome transfer studies in congenic strains can be used to isolate chromosome regions that contain BP QTL and to test directly their importance in the pathogenesis of hypertension.9 To confirm the presence of a putative BP QTL on chromosome 1 and to begin fine genetic mapping of specific variants responsible for increased blood pressure, we replaced an SHR chromosome 1 segment defined by the markers D1Mit3 and Igf2 with the corresponding chromosome region from the normotensive BN strain. We found that the systolic and diastolic BPs of the SHR congenic strain carrying the chromosome 1 segment transferred from the BN rat are significantly lower than the BPs of the progenitor SHR strain. These findings suggest that we have isolated a QTL-regulating blood pressure on chromosome 1 in the rat that appears to play a significant role in the pathogenesis of spontaneous hypertension.
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Methods |
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Strains
The SHR congenic strain was derived from a progenitor strain of SHR (SHR/Ola) descended from inbred SHR originally obtained from the National Institutes of Health. This progenitor strain of SHR is commercially available in Europe and has been maintained by brotherxsister mating at the Czech Academy of Sciences in Prague for more than 15 years. The rats were in the F48 generation when the SHR colony was established in Prague. The results of DNA fingerprint and PCR microsatellite tests have confirmed that the SHR progenitor strain is highly inbred.10 11 12
The SHR congenic strain was derived by a selective breeding protocol in which a segment of chromosome 1 from the normotensive BN/Cr strain was transferred onto the genetic background of the progenitor SHR. The coat color (C) and a microsatellite marker within the gene encoding insulin-like growth factor 2 (Igf2) were used for selection of heterozygous carriers in each back-cross generation. After 10 generations of selective back-crossing to the SHR progenitor strain, the differential chromosome segment was fixed using the markers D1Mit3 (a microsatellite marker that maps close to C) and Igf2 and maintained in the homozygous state by brotherxsister mating and selective inbreeding of the offspring. Animals of the N10F3 generation were used in the present studies. This strain was designated SHR.BN-D1Mit3/Igf2.
Chromosome 1 Mapping
To determine the length of the differential chromosome 1
segment transferred onto the SHR genetic background, we typed the
congenic strain using the following gene markers polymorphic
between the SHR and BN progenitor strains: Cype,
D1Arb12, D1Mgh5, D1Mgh6,
D1Mgh7, D1Mgh8, D1Mgh9,
D1Mgh10, D1Mgh11, D1Mgh19,
D1Mgh20, D1Mgh21, D1Mit3,
D1Mit4, D1Mit7, D1Wox6 (RCA09.01),
D1Wox10 (RCA01.20), Igf2 (D1Mgh22),
Lsn, Mt1pa, Sa, Scnn1b, and
Scnn1g. Unless otherwise specified, primers were obtained
from Research Genetics (Huntsville, Ala) with sequences as published by
Jacob et al.13 PCR primers amplifying
D1Arb12,14 D1Wox6
(RCA09.01),5 D1Wox10
(RCA01.20),5 Sa,15 and
Scnn1b7 were synthesized according to published
sequences. The map positions of D1Arb12, D1Wox10,
and D1Wox6 were determined relative to the published
chromosome 1 map of Jacob et al by performing genotyping in the same
SHRxBN F2 population.13 The "try" command of the
Mapmaker program was used to place loci in their maximum likelihood
positions. Map locations of Sa and Scnn1b were
estimated according to the map distances of Pravenec et
al.16 Scnn1g was mapped in the
SHRxBN-Lx recombinant inbred strains previously
analyzed using PCR primers amplifying around an Xcm1
restriction site present in the BN-Lx Scnn1g gene but
not the SHR gene: the upstream primer was 5'-AAA TCA ACA TGA GCT ATT
CTG C; the downstream primer was 5'-GGA CAT CCC ATC GAA GAA G. Using
the Map Manager program of Manly,17 we mapped
Scnn1g to the same location as Scnn1b (95%
confidence interval, 0 to 3 cM).18
Genotype Analysis of the
SHR.BN-D1Mit3/Igf2 Congenic Strain
The congenic status of the SHR-Chr1 strain was confirmed
by PCR analysis of the following markers polymorphic
between the SHR and BN strains: D2Mit4, D2Mit16,
D2N9119 (chr.2); D3Mit10,
D3Mit11, D3Mit15 (chr.3); D4Mgh17,
Il6, Npy (chr.4); D5Mgh8,
D5Mit1, D5Mit7 (chr.5); D6Mit8,
D6Mit9, Ighe (chr.6); D7Mgh7,
D7Mgh11, D7Mit8 (chr.7); Acaa,
D8Mgh5, D8Mgh7, D8Mit4,
D8Mit6 (chr.8); D9Mit1, D9Mit4
(chr.9); D10Mgh4, D10Mit1, D10Mit6
(chr.10); D11Mgh4, D11Mgh5, D11Mgh6
(chr.11); D12Mgh1, D12Mgh4, D12Mit8
(chr.12); D13Mit1, D13Mit4,
D13N120 (chr.13); D14Mit4,
D14Mit7, D14Mit8 (chr.14); D15Mgh2,
D15Mgh5, D15Mit3 (chr.15); D16Mit2,
D16Mit3, D16Mit6 (chr.16); D17Mit2,
D17Mit4, D17Mit7 (chr.17); D18Mgh1,
D18Mit1, D18Mit9 (chr.18); D19Mgh4,
D19Mit5, D19Mit6 (chr.19); D20Mgh1,
D20Mgh2, Tnfa (chr.20); and Arl,
DXMgh1 (chr.X). PCR primers were obtained from Research
Genetics (Huntsville, Ala)13 or synthesized in the
University of California, San Francisco Biomolecular Resource Center
according to published sequences.
Cardiovascular Phenotyping
Pulsatile arterial pressures and heart rates were
measured in unanesthetized, unrestrained male rats between 8
and 15 weeks of age. Indwelling radiotelemetry transducers were
implanted with rats under ketamine/xylazine
anesthesia and connected to catheters implanted in the
lower abdominal aorta (Datasciences).21 22 23 24 Pulsatile
pressures and heart rates were recorded in 5-second bursts every 5
minutes during the day (6 AM to 6 PM) and night
(6 PM to 6 AM) for 7 weeks. From these data,
single daytime, nighttime, and 24-hour means for systolic and
diastolic BP and heart rate were calculated for each rat
for each week of the study. Before and during the BP studies, all rats
were given tap water ad libitum and fed a standard pelleted laboratory
diet that contained 0.58% NaCl and 1.1% K. Cardiac mass was
determined by weighing the heart and correcting for body weight.
We measured blood pressure in 9 male congenic SHR.BN-D1Mit3/Igf2 rats and 12 male progenitor SHR rats in two separate studies. The weekly 24-hour mean systolic and diastolic BPs and heart rates were not different between the first and second SHR groups or between the first and second SHR.BN-D1Mit3/Igf2 groups analyzed by repeated measures ANOVA (SigmaStat, Jandel Corp). Therefore, 24-hour mean weekly BP data from the two studies were combined and analyzed using ANOVA. Cardiac mass was analyzed using the Mann-Whitney rank-sum test.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Genotype analysis of markers on chromosome 1 verified successful transfer of a defined segment of chromosome from the BN strain onto the SHR background. The minimum size of the transferred chromosome segment was delineated by markers for D1Arb12 and D1Mgh11; the maximum size of the segment was defined by the markers D1Wox6 and D1Wox10. No double recombination was observed within the homozygous portion of the differential chromosome segment (Fig 1
). The size of the chromosome segment
transferred from the BN into the SHR congenic strain is between 22 and
33 cM and includes the Sa gene and the closely linked genes
encoding the ß and subunits of the epithelial sodium channel
(Scnn1b, Scnn1g) that were associated with BP in
previous studies. Genotype results obtained with 60 widely
dispersed polymorphic microsatellite markers confirmed that the
congenic strain differs from the SHR progenitor only in the region of
chromosome 1 defined in Fig 1.
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Systolic and diastolic BPs determined by
radiotelemetry were significantly lower in the
SHR.BN-D1Mit3/Igf2 congenic strain than in the SHR
progenitor strain (Fig 2a and 2b). The strain differences in BP were
apparent after surgical recovery at 9 weeks of age and persisted over
the remaining 6 weeks of the study. Lower BPs were also observed in the
SHR.BN-D1Mit3/Igf2 congenic strain during both the daytime
and nighttime light cycles (separate nighttime and daytime data not
shown). Cardiac mass and heart rate were not significantly different
between the SHR congenic strain and the SHR progenitor (data not
shown).
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) and SHR.BN-D1Mit3/Igf2
congenic strain (n=9) (
) obtained from the weekly averages of
approximately 1000 daytime and 1000 nighttime BP measurements in each
rat. a, Systolic BP: the 24-hour average systolic
pressures of the SHR.BN-D1Mit3/Igf2 congenic strain were
significantly lower than those of the SHR progenitor strain
(P<.001). b, Diastolic BP: the
24-hour average diastolic BPs of the
SHR.BN-D1Mit3/Igf2 congenic strain were significantly lower
than those of the SHR progenitor strain (P<.001). |
Discussion |
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Studies in segregating populations derived from SHR and normotensive strains have suggested that BP QTL may exist on multiple autosomes including chromosomes 1, 2, 4, 8, 10, 13, 16, 19, and 20.5 10 11 12 25 26 27 28 29 30 31 32 33 However, there exists considerable uncertainty about the actual contribution of any of these chromosome regions to the pathogenesis of spontaneous hypertension. In the present studies, we constructed a novel congenic strain of SHR containing a genetically isolated region of chromosome 1 transferred from the BN. We found that transfer of a segment of chromosome 1 from the normotensive BN onto the SHR background is sufficient to induce a significant reduction in arterial BP. The reductions in BP were 10 to 15 mm Hg for systolic pressure and 6 to 10 mm Hg for diastolic pressure. Given that the difference in systolic BP between the progenitor SHR and BN strains is approximately 80 mm Hg, the region of chromosome 1 defined by the SHR.BN-D1Mit3/Igf2 congenic strain may account for up to 18% of the hypertension in SHR versus BN. This 10– to 15–mm Hg systolic BP difference between the SHR progenitor and SHR.BN-D1Mit3/Igf2 strains is not simply a nonspecific effect of substituting a random chromosome segment in the SHR with the corresponding chromosome region from the BN. For example, recently we found no difference in systolic or diastolic BPs measured by radiotelemetry between the SHR and an SHR-RT1.N congenic strain derived by transferring a segment of chromosome 20 containing the major histocompatibility complex from the BN-Lx strain onto the SHR background.34
The present findings are consistent with the results of previous linkage studies in which polymorphisms in the Sa and/or Scnn1b genes have cosegregated with BP in segregating populations derived by crossing the SHR or the Dahl salt-sensitive rat with normotensive strains.2 3 4 5 6 7 28 In an F2 population derived from Dahl salt-sensitive and Lewis rats, Gu et al5 detected a possible BP QTL on chromosome 1 in the vicinity of the Sa gene between D1Mit4 and Myl2. This region maps within the differential chromosome segment trapped in the SHR.BN-D1Mit3/Igf2 strain. Polymorphisms at the Sa and/or Scnn1b loci also cosegregated with BP in F2 populations derived from SHRxWistar-Kyoto rats,2 3 SHR-stroke-pronexWistar-Kyoto rats,6 and in a series of recombinant inbred strains derived from SHRxBN-Lx rats.7
Although the chromosome region isolated in the SHR.BN-D1Mit3/Igf2 congenic strain contains the Sa, Scnn1b, and Scnn1g genes, sequence analysis of these candidate genes has not revealed a clear mechanism whereby molecular variation might contribute to spontaneous hypertension.7 8 For example, we found no functionally significant sequence variation in the Scnn1b or Scnn1g genes between SHR and normotensive BN, although it is possible that regulatory mutations exist within the noncoding regions of Scnn1b or Scnn1g that influence BP (Reference 77 and unpublished observation, Kurtz et al, 1995). Of course, many other genes exist within the 22- to 33-cM differential chromosome region isolated in the SHR.BN-D1Mit3/Igf2 congenic strain. The transferred rat chromosome 1 segment is homologous to human chromosomes 16p and 11p and mouse chromosome 7. Analysis of these corresponding mouse and human chromosome regions may reveal a number of interesting candidate genes that map to the rat chromosome 1 region isolated in the SHR.BN-D1Mit3/Igf2 congenic strain.
The SHR.BN-D1Mit3/Igf2 congenic strain represents an important new model for the characterization of a gene or genes on chromosome 1 involved in the pathogenesis of spontaneous hypertension. Congenic sublines can now be derived for exclusion mapping and for refining the map positions of QTL with significant effects on BP.9 If a single gene is responsible for the significant changes in BP observed in the present study, the SHR.BN-D1Mit3/Igf2 congenic strain could ultimately allow the mapping of a BP QTL on rat chromosome 1 as a simple Mendelian locus.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants 302/96/1282 from the Grant Agency of the Czech Republic and by funding from the PECO Program of the European Commission (EURHYPGEN Project). The research of Dr Pravenec was supported in part by an international research scholar's award from the Howard Hughes Medical Institute. This work was also supported by a grant from the National Institutes of Health (Hypertension Program Project PO1 HL-35018), by funds provided by the Cigarette and Tobacco Surtax Fund of the State of California through the Tobacco Related Diseases Research Program of the University of California, grant 4RT-0362, and by a grant to Dr St. Lezin from the California Affiliate of the American Heart Association.
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Footnotes |
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Reprint requests to Michal Pravenec, PhD, Institute of Physiology, Czech Academy of Sciences, Vídenská 1083, 142 20 Prague 4, Czech Republic.
Received December 19, 1996; first decision January 31, 1997; accepted February 26, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. Ganten D. Role of animal models in hypertension research. Hypertension.. 1987;9:1-2.
2. Samani NJ, Lodwick D, Vincent M, Dubay C, Kaiser MA, Kelly MP, Lo M, Harris J, Sassard J, Lathrop M, Swales JD. A gene differentially expressed in the kidney of the spontaneously hypertensive rat cosegregates with increased blood pressure. J Clin Invest.. 1993;92:1099-1103.
3. Iwai N, Kurtz TW, Inagami T. Further evidence of the SA gene as a candidate gene contributing to the hypertension in spontaneously hypertensive rats. Biochem Biophys Res Commun.. 1992;188:64-69.[Medline] [Order article via Infotrieve]
4. Harris EL, Dene H, Rapp JP. SA gene and blood pressure cosegregation using Dahl salt-sensitive rats. Am J Hypertens.. 1996;6:330-334.
5. Gu L, Dene H, Deng AY, Hoebee B, Bihoreau M, James M, Rapp JP. Genetic mapping of two blood pressure quantitative trait loci on rat chromosome 1. J Clin Invest.. 1996;97:777-788.[Medline] [Order article via Infotrieve]
6. Lindpaintner K, Hilbert P, Ganten D, Nadal-Ginard B, Inagami T, Iwai N. Molecular genetics of the SA-gene: cosegregation with hypertension and mapping to rat chromosome 1. J Hypertens.. 1993;11:19-23.[Medline] [Order article via Infotrieve]
7. Huang H, Pravenec M, Wang J, Kren V, St Lezin EM, Szpirer C, Szpirer J, Kurtz TW. Mapping and sequence analysis of the gene encoding the beta subunit of the epithelial sodium channel in experimental models of hypertension. J Hypertens.. 1995;13:1247-1251.[Medline] [Order article via Infotrieve]
8. Shiota C, Inagami T. Lower level of SA mRNA in Wistar-Kyoto rat kidney caused by a mutation in the SA gene. Hypertension.. 1996;28:514. Abstract.
9.
Rapp JP, Deng AY. Detection and positional
cloning of blood pressure quantitative trait loci: is it
possible? Hypertension.. 1995;25:1121-1128.
10. Pravenec M, Gauguier D, Schott J, Buard J, Kren V, Bila V, Szpirer C, Szpirer J, Wang J, Huang H, St Lezin E, Spence MA, Flodman P, Printz M, Lathrop GM, Vergnaud G, Kurtz TW. Mapping of quantitative trait loci for blood pressure and cardiac mass in the rat by genome scanning of recombinant inbred strains. J Clin Invest.. 1995;96:1973-1978.
11.
Pravenec M, Kren V, Kunes J, Scicli AG, Carretero OA,
Simonet L, Kurtz TW. Cosegregation of blood pressure with a
kallikrein gene family polymorphism.
Hypertension.. 1991;17:242-246.
12. Pravenec M, Simonet L, Kren V, Kunes J, Levan G, Szpirer J, Szpirer C, Kurtz T. The rat renin gene: assignment to chromosome 13 and linkage to the regulation of blood pressure. Genomics. 1991;9:466-472.[Medline] [Order article via Infotrieve]
13. Jacob HJ, Brown DM, Bunker RK, Daly MJ, Dzau VJ, Goodman A, Koike G, Kren V, Kurtz T, Lernmark A, Levan G, Mao Y, Pettersson A, Pravenec M, Simon JS, Szpirer C, Szpirer J, Trolliet M, Winer ES, Lander ES. A genetic linkage map of the laboratory rat, Rattus norvegicus. Nat Genet.. 1995;9:63-69.[Medline] [Order article via Infotrieve]
14. Ding Y, Remmers EF, Du Y, Longman RE, Goldmuntz EA, Zha H, Kotake S, Cannon GW, Griffiths MM, Wilder RL. Genetic maps of polymorphic DNA loci on rat chromosome 1. Genomics.. 1996;36:320-327.[Medline] [Order article via Infotrieve]
15. Gu L, Dene H, Rapp JP. Three microsatellites defining four alleles for the rat Sa gene. Mamm Genome.. 1994;5:833.[Medline] [Order article via Infotrieve]
16. Pravenec M, Gauguier D, Schott J, Buard J, Kren V, Bila V, Szpirer C, Szpirer J, Wang J, Huang H, St Lezin E, Spence MA, Flodman P, Printz M, Lathrop GM, Vergnaud G, Kurtz TW. A genetic linkage map of the rat derived from recombinant inbred strains. Mamm Genome.. 1996;7:117-127.[Medline] [Order article via Infotrieve]
17. Manly KF. A Macintosh program for storage and analysis of experimental mapping data. Mamm Genome. 1993;4:303-313.[Medline] [Order article via Infotrieve]
18.
Silver J. Confidence limits for estimates of
gene linkage based on analysis of recombinant inbred
strains. J Hered. 1985;76:436-440.
19. Zha H, Wilder RL, Goldmuntz EA, Cash JM, Crofford LJ, Mathern P, Remmers EF. Linkage map of 10 polymorphic markers on rat chromosome 2. Cytogenet Cell Genet. 1993;63:117-122.[Medline] [Order article via Infotrieve]
20. Remmers EF, Goldmuntz EA, Zha H, Mathern P, Du Y, Crofford LJ, Wilder RL. Linkage map of nine loci defined by polymorphic DNA markers assigned to rat chromosome 13. Genomics.. 1993;18:277-282.[Medline] [Order article via Infotrieve]
21. Brockway B, Mills P, Azar S. A new method for continuous chronic measurement and recording of blood pressure, heart rate, and activity in the rat via radio-telemetry. Clin Exp Hypertens (A).. 1991;13:885-895.[Medline] [Order article via Infotrieve]
22. Bazil MK, Krulan C, Webb RL. Telemetric monitoring of cardiovascular parameters in conscious spontaneously hypertensive rats. J Cardiovasc Pharmacol.. 1993;22:897-905.[Medline] [Order article via Infotrieve]
23.
St Lezin EM, Pravenec M, Wong A, Wang JM, Merriouns T,
Newton S, Stec DE, Roman RJ, Lau D, Morris RC, Kurtz TW. Genetic
contamination of Dahl SS/Jr rats: impact on studies of salt-sensitive
hypertension. Hypertension.. 1994;23:786-790.
24. St Lezin EM, Pravenec M, Wong AL, Liu W, Wang N, Lu S, Jacob HJ, Roman RJ, Stec DE, Wang J, Reid IA, Kurtz TW. Effects of renin gene transfer on blood pressure and renin gene expression in a congenic strain of Dahl salt-resistant rats. J Clin Invest.. 1996;97:522-527.[Medline] [Order article via Infotrieve]
25.
Schork NJ, Krieger JE, Trolliet MR, Franchini KG, Koike
G, Krieger EM, Lander ES, Dzau VJ, Jacob HJ. A biometrical
genome search in rats reveals the multigenic basis of blood pressure
variation. Genome Res. 1995;5:164-172.
26. Jacob HJ, Lindpaintner K, Lincoln SE, Kusumi K, Bunker RK, Mao YP, Ganten D, Dzau VJ, Lander ES. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell.. 1991;67:213-224.[Medline] [Order article via Infotrieve]
27. Hilbert P, Lindpaintner K, Beckmann JS, Serikawa T, Soubrier F, Dubay C, Cartwright P, DeGouyon B, Julier C, Takahasi S, Vincent M, Ganten D, Georges M, Lathrop GM. Chromosomal mapping of two genetic loci associated with blood pressure regulation in hereditary hypertensive rats. Nature.. 1991;353:521-529.[Medline] [Order article via Infotrieve]
28. Nara Y, Nabiki T, Ikeda K, Sawamura M, Mano M, Endo J, Yamori Y. Basal high blood pressure cosegregates with the loci on chromosome 1 in the F2 generation from crosses between normotensive Wistar Kyoto rats and stroke-prone spontaneously hypertensive rats. Biochem Biophys Res Commun.. 1993;194:1344-1351.[Medline] [Order article via Infotrieve]
29. Katsuya T, Higaki J, Zhao Y, Miki T, Mikami H, Serikawa T, Ogihara T. A neuropeptide Y locus on chromosome 4 cosegregates with blood pressure in the spontaneously hypertensive rat. Biochem Biophys Res Commun.. 1993;192:261-267.[Medline] [Order article via Infotrieve]
30.
Turner ME, Johnson ML, Ely DL. Separate
sex-influenced and genetic components in spontaneously hypertensive rat
hypertension. Hypertension.. 1991;17:1097-1103.
31. Pravenec M, Klir P, Kren V, Zicha J, Kunes J. An analysis of spontaneous hypertension in spontaneously hypertensive rats by means of new recombinant inbred strains. J Hypertens.. 1989;7:217-222.[Medline] [Order article via Infotrieve]
32. Pravenec M, Kren V, Kunes J, Kurtz TW. The SHR.1N congenic strain delineates a contribution of chromosome 20 gene(s) to hypertension in the spontaneously hypertensive rat. Hypertension.. 1993;22:407. Abstract.
33. Kurtz TW, Simonet L, Kabra PM, Wolfe S, Chan L, Hjelle BL. Cosegregation of the renin allele of the spontaneously hypertensive rat with an increase in blood pressure. J Clin Invest.. 1990;85:1328-1332.
34. Kren V, Pravenec M, Lu S, Krenova D, Wang JM, Wang N, Merriouns T, Wong A, St Lezin E, Lau D, Szpirer C, Szpirer J, Kurtz TW. Genetic isolation of a region of chromosome 8 that exerts major effects on blood pressure and cardiac mass in the spontaneously hypertensive rat. J Clin Invest. 1997;99:577-581.[Medline] [Order article via Infotrieve]
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 Y. SAAD, M. R. GARRETT, and J. P. RAPP Multiple blood pressure QTL on rat chromosome 1 defined by Dahl rat congenic strains Physiol Genomics, January 19, 2001; 4(3): 201 - 214. [Abstract] [Full Text] [PDF]
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 Y. Ohno, H. Tanase, T. Nabika, K. Otsuka, T. Sasaki, T. Suzawa, T. Morii, Y. Yamori, and T. Saruta Selective Genotyping With Epistasis Can Be Utilized for a Major Quantitative Trait Locus Mapping in Hypertension in Rats Genetics, June 1, 2000; 155(2): 785 - 792. [Abstract] [Full Text]
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 J. P. Rapp Genetic Analysis of Inherited Hypertension in the Rat Physiol Rev, January 1, 2000; 80(1): 135 - 172. [Abstract] [Full Text] [PDF]
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A. F. Dominiczak, D. C. Negrin, J. S. Clark, M. J. Brosnan, M. W. McBride, and M. Y. Alexander Genes and Hypertension : From Gene Mapping in Experimental Models to Vascular Gene Transfer Strategies Hypertension, January 1, 2000; 35(1): 164 - 172. [Abstract] [Full Text] [PDF]
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B. Jeffs, C. D. Negrin, D. Graham, J. S. Clark, N. H. Anderson, D. Gauguier, and A. F. Dominiczak Applicability of a "Speed" Congenic Strategy to Dissect Blood Pressure Quantitative Trait Loci on Rat Chromosome 2 Hypertension, January 1, 2000; 35(1): 179 - 187. [Abstract] [Full Text] [PDF]
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E. St. Lezin, W. Liu, J.-M. Wang, Y. Yang, N. Qi, V. Kren, V. Zidek, T. W. Kurtz, and M. Pravenec Genetic Analysis of Rat Chromosome 1 and the Sa Gene in Spontaneous Hypertension Hypertension, January 1, 2000; 35(1): 225 - 230. [Abstract] [Full Text] [PDF]
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F. A. Wright, D. T. O'Connor, E. Roberts, G. Kutey, C. C. Berry, L. U. Yoneda, D. Timberlake, and G. Schlager Genome Scan for Blood Pressure Loci in Mice Hypertension, October 1, 1999; 34(4): 625 - 630. [Abstract] [Full Text] [PDF]
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N. Hubner, Y.-A. Lee, K. Lindpaintner, D. Ganten, and R. Kreutz Congenic Substitution Mapping Excludes Sa as a Candidate Gene Locus for a Blood Pressure Quantitative Trait Locus on Rat Chromosome 1 Hypertension, October 1, 1999; 34(4): 643 - 648. [Abstract] [Full Text] [PDF]
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E. St. Lezin, K. A. Griffin, M. Picken, M. C. Churchill, P. C. Churchill, T. W. Kurtz, W. Liu, N. Wang, V. Kren, V. Zidek, et al. Genetic Isolation of a Chromosome 1 Region Affecting Susceptibility to Hypertension-Induced Renal Damage in the Spontaneously Hypertensive Rat Hypertension, August 1, 1999; 34(2): 187 - 191. [Abstract] [Full Text] [PDF]
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 S. N. Orlov, N. C. Adragna, V. A. Adarichev, and P. Hamet Genetic and biochemical determinants of abnormal monovalent ion transport in primary hypertension Am J Physiol Cell Physiol, March 1, 1999; 276(3): C511 - C536. [Abstract] [Full Text] [PDF]
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E. St. Lezin, L. Zhang, Y. Yang, J.-M. Wang, N. Wang, N. Qi, J. S. Steadman, W. Liu, V. Kren, V. Zidek, et al. Effect of Chromosome 19 Transfer on Blood Pressure in the Spontaneously Hypertensive Rat Hypertension, January 1, 1999; 33(1): 256 - 260. [Abstract] [Full Text] [PDF]
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N. Iwai, Y. Tsujita, and M. Kinoshita Isolation of a Chromosome 1 Region That Contributes to High Blood Pressure and Salt Sensitivity Hypertension, October 1, 1998; 32(4): 636 - 638. [Abstract] [Full Text] [PDF]
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S. A. Frantz, M. Kaiser, S. M. Gardiner, D. Gauguier, M. Vincent, J. R. Thompson, T. Bennett, and N. J. Samani Successful Isolation of a Rat Chromosome 1 Blood Pressure Quantitative Trait Locus in Reciprocal Congenic Strains Hypertension, October 1, 1998; 32(4): 639 - 646. [Abstract] [Full Text] [PDF]
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J. Rapp Editorial Commentary: The Sa Gene : What Does It Mean? Hypertension, October 1, 1998; 32(4): 647 - 648. [Full Text] [PDF]
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A. P. Provoost, M. Shiozawa, R. P. E. Van Dokkum, and H. J. Jacob Transfer of the Rf-1 region from FHH onto the ACI background increases susceptibility to renal impairment Physiol Genomics, February 28, 2002; 8(2): 123 - 129. [Abstract] [Full Text] [PDF]
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M. LO, K. L. LIU, J.-R. CLEMITSON, J. SASSARD, and N. J. SAMANI Chromosome 1 blood pressure QTL region influences renal function curve and salt sensitivity in SHR Physiol Genomics, February 11, 2002; 8(1): 15 - 21. [Abstract] [Full Text] [PDF]
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Y. SAAD, M. R. GARRETT, S. J. LEE, H. DENE, and J. P. RAPP Localization of a blood pressure QTL on rat chromosome 1 using Dahl rat congenic strains Physiol Genomics, November 11, 1999; 1(3): 119 - 125. [Abstract] [Full Text] [PDF]
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