Two closely linked interactive blood pressure QTL on rat chromosome 5 defined using congenic Dahl rats

Michael R. Garrett and John P. Rapp

Department of Physiology and Molecular Medicine, Medical College of Ohio, Toledo, Ohio 43614


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Previously we reported the construction of a congenic strain, S.LEW(5), spanning a large region of rat chromosome 5. The Lewis (LEW) strain was the donor, and the Dahl salt-sensitive (S) strain was the recipient. The congenic strain included a blood pressure quantitative trait locus (QTL). In the present work, a series of nine congenic substrains were constructed from S.LEW(5) which defined two closely linked blood pressure QTL in the region previously thought to contain only one. LEW low-blood-pressure alleles at both QTL were required for a major effect on blood pressure. Neither LEW allele alone had a significant effect on blood pressure. The two QTL were localized to regions 6.3 and 4.6 cM, and these were 1.0 cM apart.

hypertension; quantitative trait loci; genetic hypertension


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
QUANTITATIVE TRAIT LOCI (QTLs) have been described for many complex quantitative phenotypes using linkage analysis in model systems. Construction of congenic strains through the QTL region has been a favorite method to confirm the existence of the QTL, followed by construction of congenic substrains to localize the QTL. This procedure is complicated somewhat when the QTL region in fact contains more than one locus influencing the phenotype. The present work describes a particularly frustrating example of two closely linked, apparently interacting loci on rat chromosome 5 influencing blood pressure in the Dahl salt-sensitive rat contrasted with the Lewis strain.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
All rats were bred and handled in our colony following institutional guidelines. Inbred Dahl salt-sensitive (SS/Jr) rats were developed in our colony (22) and will be referred to as S rats. A congenic strain, S.LEW(5), was developed and reported by us previously (10). This strain was constructed by introgressing a large segment of rat chromosome 5 from Lewis (LEW) rats into the Dahl S rat background. The LEW strain (LEW/NCrlBR) was obtained originally from Charles River Laboratories (Wilmington, MA). The introgressed LEW region contained a low-blood-pressure allele and spanned the QTL region detected in a genome scan of an F2 (S x LEW) population (10).

Congenic substrains from S.LEW(5) were constructed by crossing S.LEW(5) to S, and the F1 were intercrossed to yield a large F2 population. DNA of F2 rats was extracted from tail biopsy tissue using the DNeasy 96 Tissue Kit (Qiagen, Chartsworth, CA), and genotypes of microsatellite markers throughout the congenic region were obtained as done previously (6, 8, 10). Rats showing useful recombinant chromosomes in the congenic region were crossed to S to duplicate the recombinant chromosome, and the offspring were selectively bred by at least two generations of brother-sister mating to fix the recombinant chromosome in the homozygous state on the S background. The original congenic S.LEW(5) was the product of eight backcrosses (not counting the F1 as a backcross). The first subset of congenic strains developed from S.LEW(5) shown in Fig. 1 are the product of at least nine backcrosses, and the second set of congenic substrains in Fig. 2 developed from the first subset are the product of at least 10 backcrosses. After 10 backcrosses the genomic contribution of LEW rats outside the congenic region on average will be 1.7 cM scattered across all chromosomes.



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Fig. 1. Congenic strains for rat chromosome 5 with LEW as the donor strain on the S-rat genetic background. The linkage map is at the right, and the numbers denote map distances in centimorgans (cM). The centromere is toward the top of the map. The solid bars to the left of the linkage map indicate the extent of the donor regions homozygous for the LEW alleles for each congenic strain. The open bars on the ends of these congenic segments indicate the interval in which recombination occurred. The effect on blood pressure of each strain compared with S rats is shown by the bar graph at the bottom. Blood pressure effect is defined as the blood pressure of congenic rats (n = 20) minus blood pressure of concomitantly studied S rats (n = 20); the standard error of this difference is indicated by the thin line at the end of the blood pressure bars. Significance levels by a t-test for the blood pressure effect are shown below each bar. A negative blood pressure deviation means that the congenic strain had a lower blood pressure than concomitantly studied S rats. The 2-LOD interval from our previous genome scan (10) is shown at the right. The LOD score peak is indicated by the solid diamond symbol and was 4.5. The deduced position of the blood pressure quantitative trait locus (QTL) based on the data from the congenic strains is indicated at the left, labeled "QTL 1." *A linkage distance between markers D5Rat108 and D5Rjr1 could not be determined from the linkage panel because these markers are very close together. However, a crossover between these markers occurred in the development of strain S.LEW(5) x 6, which defined the order of markers and the end of the congenic strain S.LEW(5) x 6.

 


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Fig. 2. Further derivation of congenic strains for rat chromosome 5. The format is the same as Fig. 1. Strains S.LEW(5) x 6 and S.LEW(5) x 5 are from Fig. 1. The other four strains were derived from S.LEW(5) x 6 and are labeled S.LEW(5) x 6 x 6, S.LEW(5) x 6 x 9, S.LEW(5) x 6 x 10, and S.LEW(5) x 6 x 11. The data indicate the presence of two QTL (labeled "QTL 1" and "QTL 2"), both of which are required to retain the LEW allele in a given congenic strain in order for a significant blood pressure effect to be observed; the double-headed arrow between QTL 1 and QTL 2 is meant to imply this interaction. QTL 1 here is the same as QTL 1 in Fig. 1. See legend to Fig. 1 for description of the asterisk.

 
Blood pressure of a given congenic strain was always compared with concomitantly bred and raised S rats. Briefly, 20 male S and 20 male congenic rats were age matched, housed in the same cages, and studied concomitantly. Starting at 40–42 days of age, the rats were fed 2% NaCl diet (Teklad diet TD 94217; Harlan Teklad, Madison, WI). Blood pressure was taken on four consecutive days starting the 24th day on the 2% NaCl diet. Blood pressure measurements were made on the conscious restrained rat warmed to 28°C by the tail-cuff method using semi-automated equipment (IITC; Life Science Instruments, Woodland Hills, CA) (2). On each day, three consistent readings were made by an operator who did not know the identity of a given rat. The final blood pressure of a rat was taken as the average of the four consecutive day determinations. Strain comparisons were made by a t-test using programs from SPSS (Chicago, IL). All congenic rats on which blood pressure was taken were genotyped after euthanasia by CO2 inhalation, to be sure all were the expected genotype throughout the congenic and flanking regions.

The chromosome 5 linkage maps were made using the MAPMAKER/EXP program (Whitehead Institute, Cambridge, MA) (17, 18). Rat microsatellite markers were obtained from Research Genetics (Huntsville, AL) or synthesized based on sequence data in the literature (5, 16, 28, 30). For comparative mapping of the QTL region across species, all of the genes that map to our QTL region in mouse and human were checked for the availability of rat sequence data. If rat sequence was available for any gene that mapped to the QTL region in mouse or human, then a primer set was developed and placed on the rat radiation hybrid map. The genes placed on the rat radiation hybrid map in this way were Pde4b, Nrd1, Cpt2, Urod, Ugn, Ppt, and Glur7. A marker for Jun was from Chua et al. (3). The radiation hybrid map was constructed using data obtained from the Rat Genome Database at the Medical College of Wisconsin (http://www.rgd.mcw.edu) and the Wellcome Trust Centre for Human Genetics (http://www.well.ox.ac.uk/rat_mapping_resources). Markers not already on the radiation hybrid map from these two sources, including markers denoted as D5Mco (Medical College of Ohio microsatellite markers) and genes Jun, Pde4b, Nrd1, Cpt2, Urod, Ugn, Ppt, and Glur7, were mapped by testing all 106 samples in the rat radiation hybrid panel (Research Genetics). Primers for these markers are on our website (http://www.mco.edu/depts/physiology/research). The regions in mouse and human homologous to our blood pressure QTL region were identified using the Mouse Genome Informatics database (http://www.informatics.jax.org) and Online Mendelian Inheritance in Man (OMIM) at The National Center for Biotechnology (http://www.ncbi.nlm.nih.gov).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Figure 1 shows the first iteration of congenic substrains developed from our original congenic strain S.LEW(5). Consider first the three strains S.LEW(5) x 4, S.LEW(5) x 6, and S.LEW(5) x 5, encompassing various segments of the upper part of the original strain in Fig. 1. The longer congenic segments in S.LEW(5) x 4 and S.LEW(5) x 6 obviously retain the QTL allele for lowering blood pressure relative to S rats, whereas the shorter congenic segment in S.LEW(5) x 5 clearly does not. In a separate experiment not shown in Fig. 1, strains S.LEW(5) x 6 and S.LEW(5) x 5 were compared directly. S.LEW(5) x 6 lowered blood pressure 28.8 ± 5.06 mmHg (P < 0.0001) compared with S.LEW(5) x 5, thus confirming the difference between these two strains.

Unfortunately, S.LEW(5) x 5 is shorter at both ends than S.LEW(5) x 6. This arose because when S.LEW(5) x 5 was constructed, inadequate markers were available to monitor the upper end of this congenic segment. Thus looking only at these strains from the technical standpoint, the QTL could be either in the upper differential segment between markers D5Uwm12 and D5Uwm14, or in the lower differential segment between markers D5Uwm31 and D5Rjr1. Figure 1, however, also shows the 2-LOD interval for the QTL from our genome scan (10) (LOD, "logarithm of the odds ratio"). This 2-LOD interval includes the lower segment between D5Uwm31 and D5Rjr1, but the upper segment between D5Uwm12 and D5Uwm14 is >30 cM outside of the 2-LOD interval (Fig. 1). Thus the lower segment is the more rational target for the QTL. This is confirmed by congenic segments coming from the bottom of Fig. 1. Strain S.LEW(5) x 3 crosses the putative QTL region and shows a significant effect of lowering blood pressure relative to S rats. The shorter strain from the bottom S.LEW(5) x 2 obviously does not contain the target QTL, because it does not lower blood pressure relative to S; quite the opposite, it raises blood pressure slightly relative to S. Thus the differential segment defined by S.LEW(5) x 3 and S.LEW(5) x 2 reinforces the location of the QTL as indicated in Fig. 1, where it is designated as QTL 1.

Figure 2 shows a second iteration of four congenic substrains constructed from strain S.LEW(5) x 6 to better define the QTL 1 region defined in Fig. 1 between D5Uwm31 and D5Rjr1. Interestingly, the shortest congenic segments spanning the target QTL 1 region, i.e., strains S.LEW(5) x 6 x 10 and S.LEW(5) x 6 x 11 showed only marginally significant blood pressure effects of 6 to 8 mmHg lower than S (Fig. 2), not the robust response of ~20 mmHg expected based on the data in Fig. 1. But, as the congenic segment was made longer in the proximal direction, i.e., strains S.LEW(5) x 6 x 9 and S.LEW(5) x 6 x 6, the major significant blood pressure effect of 20 mmHg similar to the progenitor strain S.LEW(5) x 6 was again observed (Fig. 2).

The above situation implies the existence of a second QTL in the region proximal to QTL 1. The location of such a QTL can be deduced from the data in Fig. 2. Consider for a moment only the data from the second iteration strains S.LEW(5) x 6 x 6, S.LEW(5) x 6 x 9, S.LEW(5) x 6 x 10, and S.LEW(5) x 6 x 11. The two shortest strains lack the significant blood pressure effect seen in the two longer strains. The differential segment between strains S.LEW(5) x 6 x 9 and S.LEW(5) x 6 x 10 defines the position of a QTL. This is labeled "QTL 2" in Fig. 2 and lies between markers D5Rat154 and D5Uia8. Note, however, that analogous to the situation with QTL 1, the existence of QTL 2 is not confirmed by strain S.LEW(5) x 5, which crosses the QTL 2 region but largely lacks the QTL 1 segment.

Final consideration of Fig. 2 shows that 1) strains with congenic segments that contain only QTL 1 or QTL 2 do not show a blood pressure effect and 2) strains with congenic segments that contain both QTL 1 and QTL 2 do show a marked blood pressure effect. This implies that QTL 1 and QTL 2 alleles from the LEW genome are both required to create an observable QTL effect on chromosome 5 in the S vs. LEW comparison.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
There is a reasonable amount of literature associating blood pressure and related phenotypes to rat chromosome 5; see Rapp (21) for a review. Briefly, two regions of chromosome 5 have been of interest, the distal telomeric region containing the locus for atrial natriuretic peptide (ANP) and the central chromosomal region under study here. It is worth noting that ANP was incorrectly mapped to the center of chromosome 5 (15) but subsequently corrected to the telomeric location (1).

The telomeric region around ANP was shown to be associated with blood pressure in linkage studies using spontaneously hypertensive rats (SHR) crossed to Wistar-Kyoto (WKY) (32, 33). This region is, however, clearly distinct from the congenic region studied here in Dahl rats. The telomeric region was also linked to stroke latency in a cross of stroke-prone SHR (SHRSP) and SHR (25) and more recently with cardiac hypertrophy in a cross of WKY and hyperactive WKY (WKY HA) (7).

The central region of rat chromosome 5 was of initial interest to us, because genetic markers for endothelin-2 (Edn2) were associated with blood pressure in our F2 (S x LEW) studies (4, 10). And, of course, the construction of the congenic strain (10) used here as starting material established the existence of a blood pressure QTL. Edn2 is eliminated as a candidate gene in the present work, however, because it is well outside of the QTL region defined by the congenic substrains (Fig. 1).

The central chromosome 5 region is also of interest to others studying the effects of arachidonic acid metabolites on renal function in Dahl S rats (27) or SHR (28), because the cytochromes P-450 producing biologically active products from arachidonic acid are in the central region of chromosome 5. The marker D5Rjr1 developed by Stec et al. (28), which spans a repeated element in the P450A1 locus (28), is at the very edge, but outside of, our congenic region as defined by the distal end of congenic substrain S.LEW(5) x 6 in Fig. 1. The central region of rat chromosome 5 has also been associated with a stroke phenotype in a cross of SHRSP and WKY (15). The phenotype was the infarct size following ligation of the distal middle cerebral artery. In this study, no blood pressure effect was seen colocalizing with the stroke infarct size phenotype, possibly because the rats were not challenged with a high-salt diet.

Our data imply that the two closely linked blood pressure QTL in the central part of rat chromosome 5 interact, since both were required for a significant blood pressure effect, but neither alone gave a significant effect. We have previously seen that multiple, largely additive, blood pressure QTL reside on the same chromosome and are detected by the construction of a series of congenic strains. This was observed using Dahl rats for chromosome 1 (26), chromosome 2 (11), and chromosome 10 (12) and using SHR for chromosome 1 (9). It can be argued that the appearance of a large effect QTL in linkage analysis is likely to be due to the clustering of more than one causative locus. This certainly makes identification of individual loci more difficult, as a large effect QTL breaks up into multiple loci, each of which individually has a small effect or no effect due to the requirement for the presence of specific alleles at linked loci.

Potentially interacting loci on the same chromosome have also been observed using congenic strains for phenotypes other than blood pressure. In the non-obese diabetic (NOD) mouse, three linked loci on mouse chromosome 6 (24) and three linked loci on mouse chromosome 3 (19) have been described for controlling insulin-dependent diabetes mellitus. Iakoubova et al. (14) also presented data interpreted to indicate two linked loci both contributing to the severity of recessive polycystic kidney disease in the mouse.

With two linked interactive QTL, the problem arises as how best to localize each one. If the ability to observe one depends on the presence of the other, then obviously a congenic strain spanning both can be shortened progressively from each end. This will hold one QTL constant while localizing the other. This is essentially what was done in mapping a cluster of QTL for diabetes in the NOD mouse (19).

Figure 3 shows a rat radiation hybrid map of our congenic region and comparative regions for mouse chromosome 4 and the corresponding human cytogenic locations of known genes on the rat radiation hybrid map. Two genome scans for linkage to blood pressure have been done in the mouse. In one study (29), using a backcross population derived from C57BL/6J and A/J mice, the strongest blood pressure QTL was seen on mouse chromosome 4, with peaks at mouse markers D4Mit214 and D4Mit164. These markers are at positions 18 and 28 cM, respectively, on mouse chromosome 4 and are clearly far from our rat QTL, which corresponds to the region of mouse chromosome 4 from 44 to 52 cM (Fig. 3). Another genome scan in mice using strains of hypertensive mice selectively bred for high and low blood pressure and including crosses to Mus spretus did not detect a blood pressure QTL on mouse chromosome 4 (31).



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Fig. 3. Comparative maps for rat, mouse, and human. The rat radiation hybrid (RH) map is at the left and also shows the positions of QTL 1 and QTL 2 based on Figs. 1 and 2. The center column gives the cytogenetic location on human chromosome 1 for known genes on the rat radiation hybrid map. The linkage map for mouse chromosome 4 is shown at the right. Known genes are shown in bold font.

 
The blood pressure QTLs on rat chromosome 5 correspond to the human chromosome 1p31 to 1p34 region (Fig. 3). Several studies have found genetic markers on the human chromosome 1p arm that were associated with hypertension. These include D1S1612 on 1p36 (20), D1S2834 on 1p36 (13), and D1S551 on 1p22 (23). Unfortunately, neither the human studies nor our present rat data are of sufficient resolution to determine whether the human and rat QTLs are likely to be the same.


    ACKNOWLEDGMENTS
 
This work was supported by grants to J. P. Rapp from the National Institutes of Health and by the Helen and Harold McMaster Endowed Chair in Biochemistry and Molecular Biology.


    FOOTNOTES
 
Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).

Address for reprint requests and other correspondence: J. P. Rapp, Dept. of Physiology and Molecular Medicine, Medical College of Ohio, 3035 Arlington Ave., Toledo, OH 43614-5804 (E-mail: jrapp{at}mco.edu).

10.1152/physiolgenomics.00080.2001.


    References
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. Brosnan MJ, Clark JS, Jeffs B, Negrin CD, Van Vooren P, Arribas SM, Carswell H, Aitman TJ, Szpirer C, MacRae IM, and Dominiczak AF. Genes encoding atrial and brain natriuretic peptides as candidates for sensitivity to brain ischemia in stroke-prone hypertensive rats. Hypertension 33: 290–297, 1999.[Abstract/Free Full Text]
  2. Bunag R and Butterfield J. Tail-cuff blood pressure measurement without external preheating in awake rats. Hypertension 4: 898–903, 1982.[Abstract]
  3. Chua SC Jr, Hansen MH, Truett GE, and Leibel RL. Utility of a C-Jun microsatellite marker in determining gene dosage for fatty (fa). Obes Res 1: 475–480, 1993.
  4. Deng AY, Dene H, Pravenec M, and Rapp JP. Genetic mapping of two new blood pressure quantitative trait loci in the rat by genotyping endothelin system genes. J Clin Invest 93: 2701–2709, 1994.[ISI][Medline]
  5. Deng AY, Jackson CM, Hoebee B, and Rapp JP. Mapping of rat chromosome 5 markers generated from chromosome-sorted DNA. Mamm Genome 8: 549–553, 1997.[ISI][Medline]
  6. Deng AY and Rapp JP. Cosegregation of blood pressure with angiotensin converting enzyme and atrial natriuretic peptide receptor genes using Dahl salt-sensitive rats. Nat Genet 1: 267–272, 1992.[ISI][Medline]
  7. Deschepper CF, Masciotra S, Zahabi A, BoutinGanache I, Picard S, and Reudelhuber TL. Functional alterations of the Nppa promoter are linked to cardiac ventricular hypertrophy in WKY/WKHA rat crosses. Circ Res 88: 223–228, 2001.[Abstract/Free Full Text]
  8. Dukhanina OI, Dene H, Deng AY, Choi CR, Hoebee B, and Rapp JP. Linkage map and congenic strains to localize blood pressure QTL on rat chromosome 10. Mamm Genome 8: 229–235, 1997.[ISI][Medline]
  9. Frantz S, Clemitson JR, Bihoreau MT, Gauguier D, and Samani NJ. Genetic dissection of region around the Sa gene on rat chromosome 1. Evidence for multiple loci affecting blood pressure. Hypertension 38: 216–221, 2001.[Abstract/Free Full Text]
  10. Garrett MR, Dene H, Walder R, Zhang QY, Cicila GT, Assadnia S, Deng AY, and Rapp JP. Genome scan and congenic strains for blood pressure QTL using Dahl salt-sensitive rats. Genome Res 8: 711–723, 1998.[Abstract/Free Full Text]
  11. Garrett MR and Rapp JP. Multiple blood pressure QTL on rat chromosome 2 defined by congenic Dahl rats. Mamm Genome 13: 41–44, 2002.[ISI][Medline]
  12. Garrett MR, Zhang X, Dukhanina OI, Deng AY, and Rapp JP. Two linked blood pressure quantitative trait loci on chromosome 10 defined by Dahl rat congenic strains. Hypertension 38: 779–785, 2001.[Abstract/Free Full Text]
  13. Glenn CL, Wang WYS, Benjafield AV, and Morris BJ. Linkage and association of tumor necrosis factor receptor 2 locus with hypertension, hypercholesterolemia and plasma shed receptor. Hum Mol Genet 9: 1943–1949, 2000.[Abstract/Free Full Text]
  14. Iakoubova O, Dushkin H, Pacella L, and Beier DR. Genetic analysis of modifying loci on mouse chromosome 1 that affect disease severity in a model of recessive PKD. Physiol Genomics 1: 101–105, 1999.[Medline]
  15. Jeffs B, Clark JS, Anderson NH, Gratton J, Brosnan MJ, Gauguier D, Reid JL, MacRae IM, and Dominiczak AF. Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus. Nat Genet 16: 364–367, 1997.[ISI][Medline]
  16. Lan H, Shepel LA, Haag JD, and Gould MN. Linkage mapping of rat chromosome 5 markers generated from chromosome-specific libraries. Mamm Genome 10: 687–691, 1999.[ISI][Medline]
  17. Lander E, Green P, Abrahamson J, Barlow A, Daly M, Lincoln S, and Newburg L. Mapmaker: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics 1: 174–181, 1987.[Medline]
  18. Lincoln S, Daly M, and Lander E. Constructing Genetic Maps with Mapmaker/Exp. 3.0 (3rd ed.). Whitehead Institute Technical Report, 1992.
  19. Lyons PA, Armitage N, Lord CJ, Phillips MS, Todd JA, Peterson LB, and Wicker LS. High-resolution congenic mapping of the type 1 diabetes loci Idd10 and Idd18 in the NOD mouse. Diabetes 50: 2633-2637, 2001.
  20. Pan TH, Chen JW, Fann C, Jou YS, and Wu SY. Linkage analysis with candidate genes: the Taiwan young-onset hypertension genetic study. Hum Genet 107: 210–215, 2000.[ISI][Medline]
  21. Rapp JP. Genetic analysis of inherited hypertension in the rat. Physiol Rev 80: 135–172, 2000.[Abstract/Free Full Text]
  22. Rapp JP and Dene H. Development and characteristics of inbred strains of Dahl salt-sensitive and salt-resistant rats. Hypertension 7: 340–349, 1985.[Abstract]
  23. Rice T, Rankinen T, Province MA, Chagnon YC, Perusse L, Borecki IB, Bouchard C, and Rao DC. Genome-wide linkage analysis of systolic and diastolic blood pressure: the Quebec family study. Hypertens Genet 102: 1956–1963, 2000.
  24. Rogner UC, Boitard C, Morin J, Melanitou E, and Avner P. Three loci on mouse chromosome 6 influence onset and final incidence of type 1 diabetes in NOD.C3H congenic strains. Genomics 74: 163–171, 2001.[ISI][Medline]
  25. Rubattu S, Volpe M, Kreutz R, Ganten U, Ganten D, and Lindpaintner K. Chromosomal mapping of quantitative trait loci contributing to stroke in a rat model of complex human disease. Nat Genet 13: 429–434, 1996.[ISI][Medline]
  26. Saad Y, Garrett MR, and Rapp JP. Multiple blood pressure QTL on rat chromosome 1 defined by Dahl rat congenic strains. Physiol Genomics 4: 201–214, 2001.[Abstract/Free Full Text]
  27. Stec DE, Deng AY, Rapp JP, and Roman RJ. Cytochrome P-4504A genotype cosegregates with hypertension in Dahl S rats. Hypertension 27: 564–568, 1996.[Abstract/Free Full Text]
  28. Stec DE, Trolliet MR, Krieger JE, Jacob HJ, and Roman RJ. Renal cytochrome P-4504A activity and salt sensitivity in spontaneously hypertensive rats. Hypertension 27: 1329–1336, 1996.[Abstract/Free Full Text]
  29. Sugiyama F, Churchill GA, Higgins DC, Johns C, Makaritsis KP, Gavras H, and Paigen B. Concordance of murine quantitative trait loci for salt-induced hypertension with rat and human loci. Genomics 71: 70–77, 2001.[ISI][Medline]
  30. Walder RY, Garrett MR, McClain AM, Beck GE, Brennan TMH, Kramer NA, Kanis AB, Mark AL, Rapp JP, and Sheffield VC. Short tandem repeat polymorphic markers for the rat genome from marker-selected libraries. Mamm Genome 9: 1013–1021, 1998.[ISI][Medline]
  31. Wright FA, O’Connor DT, Roberts E, Kutey G, Berry CC, Yoneda LU, Timberlake D, and Schlager G. Genome scan for blood pressure loci in mice. Hypertension 34: 625–630, 1999.[Abstract/Free Full Text]
  32. Zhang L, Summers KM, and West MJ. Cosegregation of genes on chromosome 5 with heart weight and blood pressure in genetic hypertension. Clin Exp Hypertens 18: 1073–1087, 1996.[ISI][Medline]
  33. Zhang L, Xu D, West MJ, and Summers KM. Association of the brain natriuretic peptide gene with blood pressure and heart weight in the rat. Clin Exp Pharmacol Physiol 24: 442–444, 1997.[ISI][Medline]