Multiple blood pressure QTL on rat chromosome 1 defined by Dahl rat congenic strains
YASSER SAAD,
MICHAEL R. GARRETT and
JOHN P. RAPP
Department of Physiology and Molecular Medicine, Medical College of Ohio, Toledo, Ohio 43614-5804
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ABSTRACT
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A series of congenic strains were constructed in which segments of chromosome (chr) 1 from Lewis (LEW) rats were introgressed into the Dahl salt-sensitive (S) strain. Three blood pressure quantitative trait loci (QTL) were defined. Two of these (QTL 1a and QTL 1b) were closely linked in the region between 1q31 and 1q35. The third blood pressure QTL (QTL region 2) was close to the centromere between 1p11 and 1q12, which includes the candidate gene Slc9a3 for sodium/hydrogen exchange. The blood pressure QTL 1a and QTL 1b defined here overlap significantly with QTL for disease phenotypes of renal failure, stroke, ventricular mass, and salt susceptibility defined in other rat strains, implying that these disease phenotypes and our blood pressure phenotype have causes in common. QTL 1b also corresponded approximately with a blood pressure QTL described on human chr 15. The QTL region 2 corresponded approximately with blood pressure QTL described on mouse chr 10 and human chr 6.
hypertension; salt sensitivity; quantitative trait loci; heart weight; sodium/hydrogen exchange; Slc9a3
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INTRODUCTION
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GENETIC ANALYSIS OF BLOOD pressure variation utilizing hypertensive rat strains is a reasonably advanced field and has been reviewed (10, 17, 32). Rat chromosome (chr) 1 has been of particular interest because it contains quantitative trait loci (QTL) not only for blood pressure but also for renal failure, stroke, and ventricular mass. It is of special interest to determine the relationships and overlap of the QTL for these disease phenotypes. The present article utilizes congenic strains to define the blood pressure QTL on rat chr 1 in a comparison of hypertensive Dahl salt-sensitive (S) rats with normotensive Lewis (LEW) rats. Three separate blood pressure QTL are defined, and these overlap with QTL for related disease phenotypes defined in other rat strains.
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MATERIALS AND METHODS
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Strains.
Inbred Dahl salt-sensitive (SS/Jr) rats were from our colony, and the Lewis rats (LEW/NCrlBR) were obtained from Charles River Laboratories (Wilmington, MA), and will be referred to as S and LEW, respectively. Congenic substrains (Chr1 x 3) x 2, (Chr1 x 3) x 3, (Chr1 x 3) x 4, (Chr1 x 3) x 6, (Chr1 x 3) x 12, and (Chr1 x 3) x 14 were constructed from the progenitor congenic Chr1 x 3, strain which was described previously (36). Briefly, the congenic substrains were established by screening for recombinants in an F2 population obtained by crossing Chr1 x 3 and the S strain. The desired recombinants contained varying sized fragments of the introgressed LEW rat chr 1 segment contained in congenic strain Chr1 x 3. These recombinant chromosomes were fixed in homozygous form in a congenic substrain by crossing to S rats to duplicate the recombinant chromosome followed by selective breeding to obtain a homozygous donor chromosomal segment on the S background. Another congenic strain S.LEW (D1Mco4) was constructed de novo using the standard breeding scheme for construction of a congenic strain as described previously (12). Subsequently, congenic substrains D1Mco4 x 1, D1Mco4 x 2 and D1Mco4 x 5 were derived from the congenic strain S.LEW (D1Mco4) as described above for the Chr1 x 3 series.
Genetic markers.
A number of markers were obtained from established resources to improve the rat chr 1 genetic linkage map. These markers were used to genotype an F2 (S x LEW) population of at least 92 rats and were mapped on chr 1 using MAPMAKER/EXP obtained from Dr. Eric Lander (Whitehead Institute, Cambridge, MA) (27, 28). D1Arb markers were developed by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (http://www.nih.gov/niams/scientific/ratgbase/index.htm). D1Got markers were developed by the Wellcome Trust Center for Human Genetics (http://www.well.ox.ac.uk/rat_mapping_resources) (44). D1Rat markers were developed by the Whitehead Institute for Biomedical Research (http://www.genome.wi.mit.edu). Giraudeau et al. (14) provided the D1Cebr1 marker. D1Mco markers developed at the Medical College of Ohio are on our web site (http://www.mco.edu/depts/physiology/research).
Genotyping.
PCR-based genotyping with microsatellite markers was done as described earlier (15). Congenic substrain DNA was extracted from a tail biopsy using the QIAamp Tissue Kit (Qiagen, Chartsworth, CA). The F2 population DNA used in linkage map construction and the control DNA samples obtained from rat strains S and LEW were extracted from liver (3).
Blood pressure determination.
Rats were weaned at 30 days of age to low-salt (0.3% NaCl) Harlan Teklad diet 7034 (Madison, WI). Twenty male congenic substrain rats were matched by age and weight with 20 male S control rats and were caged in 10 cages, each cage containing 2 congenic and 2 S rats. Some comparisons involved testing two different congenic substrains along with the same S rat group. In these comparisons, 20 male rats of each congenic substrain were age- and weight-matched to 20 male S rats. The 60 rats were distributed evenly in 30 cages, with each cage containing 2 rats (one congenic substrain with S or one of each congenic substrain). In any case when 4042 days old, the rats were fed a 2% NaCl Harlan Teklad diet, TD94217, for 24 days. Systolic blood pressure was measured using the tail cuff method on conscious restrained rats warmed to 28°C using semiautomatic equipment from IITC (Woodland Hills, CA). Blood pressure was measured once a day for four consecutive days (days 2428 on 2% NaCl diet). The blood pressure value of each day was the average of three to four consistent readings. The final blood pressure value used was the average blood pressure value of the 4 days. Rats were euthanized with CO2, and body and heart weights were measured.
Statistical analysis of congenic substrain and S rat blood pressures.
For each congenic substrain tested, the following variables were collected: body weight (g), blood pressure (mmHg), heart weight (mg), and relative heart weight (the ratio of heart weight to final body weight, in mg/g). An independent samples t-test (S vs. a single congenic substrain) or a one-way ANOVA with the Tukey post hoc test of comparisons (S vs. 2 congenic substrains) was done using the SPSS software (Chicago, IL). In experiments where there was a significant difference in body weight between S and a congenic strain, heart weight was corrected for differences in body weight based on the regression of heart weight on body weight (31). The corrected heart weight values were used in place of the measured values for those comparisons.
Radiation hybrid mapping.
A number of resources were used to compose the radiation hybrid maps for our regions of interest. The markers used were chosen to be ones that were associated with known genes, but other markers without gene assignments were also used. These markers included polymorphic and nonpolymorphic (S vs. LEW) markers, expressed sequence tags, and D1Bda markers (24). Markers polymorphic between S and LEW were directly from our linkage map. A list of markers not polymorphic between S and LEW was compiled from established web sites: 1) the composite linkage maps at The Whitehead Institute for Biomedical Research (http://www.genome.wi.mit.edu); 2) the radiation hybrid maps at The Wellcome Trust Centre for Human Genetics (http://www.well.ox.ac.uk/rat_mapping_resources) (44); and 3) the integrated genetic linkage and radiation hybrid maps at The Laboratory for Genetic Research at The Medical College of Wisconsin (http://goliath.ifrc.mcw.edu/LGR) (41).
Most of the radiation hybrid data were obtained from the European Bioinformatics Institute (ftp://ftp.ebi.ac.uk/pub/databases/RHdb) and some were obtained from The Wellcome Trust Centre for Human Genetics. The expressed sequence tag data were obtained from the University of Iowa (http://ratEST.uiowa.edu). Radiation hybrid data for D1Bda25, D1Bda26, and D1Bda27 were obtained from Marie-Therese Bihoreau and Dominique Gauguier (24). All markers were placed onto the framework map (41) using the radiation hybrid map server provided by The Laboratory for Genetic Research at The Medical College of Wisconsin. Markers not already on the radiation hybrid map were mapped using the radiation hybrid panel (Research Genetics, Huntsville, AL).
Comparative mapping.
A number of online databases provided valuable information regarding the cytogenetic position of genes and gene homologies between the rat, mouse, and human genes associated with genetic markers. Rat gene localizations on the cytogenetic map were obtained from The Rat Genome Database (http://ratmap.gen.gu.se) and The Wellcome Trust Centre for Human Genetics (44). Mouse syntenic regions were identified using The Mouse Genome Informatics database (http://www.informatics.jax.org). This web site also gives a list of known genes localized to the syntenic region and their homologies to rat genes. Similarly, the same web site provides information about gene homology between the mouse and human. The National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov) also provided valuable information regarding cytogenetic position of human genes and mouse and human gene homologies. Previously published comparative maps were used to confirm synteny and gene locations (1, 8, 13, 4244).
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RESULTS
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Figure 1 shows the rat chr 1 linkage map for genetic markers that are polymorphic between S and LEW rats. This map contains 153 more markers than the linkage map previously published by us (36). This brings the total number of markers to 276. These markers span the entire length of rat chr 1 (167.4 cM) with an average density of 1.6 markers per cM. The largest segment of chromosome lacking markers was 6.4 cM. The map is important for defining our congenic segments and for locating QTL described by others on rat chr 1.


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Fig. 1. An improved rat chromosome 1 (chr 1) linkage map. A total of 276 markers span the entire length of the chromosome. The numbers on the left of the genetic map represent map distances in centimorgans (cM) with Kosambis correction. The map was constructed from an F2 (S x LEW) population with a minimum of 92 rats typed at each locus. Note that to get the map to a reasonable size for illustration, the intervals marked with an asterisk (*) were not drawn to scale. Genes associated with markers are given in parentheses. The locations of quantitative trait loci (QTL) for blood pressure defined by analysis of congenic strains are also indicated. LEW, Lewis rats; S, Dahl salt-sensitive strain.
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Figure 2 defines eight congenic strains in each of which a segment of LEW chr 1 was placed on the S rat genetic background. The blood pressure effect of each strain is given at the top of the diagram. Complete data for blood pressure, heart weight, body weight, and heart weight/body weight ratio are given in Table 1.

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Fig. 2. Congenic substrains derived from Chr1 x 3 used to define QTL 1a and QTL 1b. The bars to the right of the linkage map designate the extent of congenic segments introgressed from LEW into S rats. The open ends of these bars indicate the interval in which recombination occurred. A hatched zone indicates a segment that was segregating at the time blood pressure was studied. Strains Chr1 x 3 and Chr1 x 15 are from a previous publication (36). Top: a graphical illustration of the blood pressure effect from each strain as a deviation of the congenic strain value from the control S value. A negative bar indicates that the congenic strain had a lower blood pressure than concomitantly studied S rats. A solid blood pressure bar means that the blood pressure difference was statistically significant (P < 0.0001), and an open blood pressure bar designates a nonsignificant (P > 0.05) difference. For comparison, four congenic strains constructed by others to test the blood pressure effect to the Sa gene are included at the right (11, 18, 23, 39). Also shown at the right are QTL regions identified by linkage analysis by others for other traits of interest: SS1b, blood pressure salt susceptibility locus (48); STR1, stroke locus (35); Rf-2, renal failure locus (5); Map-1, mean arterial pressure locus (20); Lvm-2, blood pressure independent ventricular mass locus (20). An asterisk (*) indicates a map distance not drawn to scale.
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Most of the strains in Fig. 2 are derived from congenic strain Chr1 x 3 that was previously shown by us to contain a blood pressure QTL (36). This is arbitrarily referred to here as QTL region 1. Figure 2 shows, however, that two blood pressure QTL are contained in the congenic segment of strain Chr1 x 3. The proximal QTL, labeled QTL 1a in Fig. 2, is defined by the fact that congenic substrain (Chr1 x 3) x 14 has a significant effect on blood pressure (-35 mmHg, P < 0.0001), whereas the congenic substrain (Chr1 x 3) x 12 does not. This implies that a QTL lies in the 8.2-cM differential segment between D1Mgh7 and D1Mco36. A second more distal QTL, labeled QTL 1b in Fig. 2, is defined by the fact that substrain (Chr1 x 3) x 2 does not overlap with the QTL 1a segment, but (Chr1 x 3) x 2 does have a significant blood pressure effect (-27 mmHg, P < 0.0001). Thus there must be a QTL between D1Rat35 and D1Rat49 that is the maximal possible introgressed region of substrain (Chr1 x 3) x 2. It is possible to define this QTL further by the fact that strain Chr1 x 15, which lacks a blood pressure effect, overlaps the distal end of (Chr1 x 3) x 2. This narrows the QTL 1b region to the 13.5-cM interval between D1Rat35 and D1Rat131 (Fig. 2). The blood pressure data defining QTL 1a and QTL 1b is corroborated by the heart weight data. Thus for every strain for which there was a significant lowering effect on blood pressure compared with S rats, there was also a significant effect to decrease heart weight as measured by either heart weight per se or heart weight/body weight ratio (Table 1).
In our linkage analysis of QTL on chr 1 (12, 15), it was obvious that a large region of the chromosome potentially contained multiple QTL. To extend congenic strain analysis to other potential QTL, an additional congenic strain was constructed de novo centromeric to the QTL described above. This new congenic strain was constructed by introgressing a segment of chr 1 from LEW rats into the S rat background. The strain is designated S.LEW (D1Mco4), and the region it covers is shown in Fig. 3. This strain did have a significant effect on blood pressure (-30 mmHg, P < 0.0001). Figure 3 shows that the distal portion of S.LEW(D1Mco4) overlaps with QTL 1a described above. But its blood pressure effect is not due entirely to QTL 1a, because substrains D1Mco4 x 1, D1Mco4 x 2, and D1Mco4 x 5 at the proximal end of S.LEW(D1Mco4) do not overlap with QTL 1a, but they also do have significant blood pressure effects ranging from -14 to -22 mmHg (P < 0.001). Thus from Fig. 3 it was possible to define an additional QTL on chr 1 that is designated "QTL region 2" in Fig. 3 and extends 17 cM from D1Uia8 to D1Rat18. The blood pressure data for QTL region 2 was also corroborated by significant changes in heart weight (Table 1).

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Fig. 3. Congenic strains used to define blood pressure QTL region 2 located near the centromere of rat chr 1. The format is the same as Fig. 2. The salt susceptibility region (SS1a) identified by linkage analysis by Yagil et al. (48) included for comparison.
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An incidental finding is a possible QTL for body weight. Substrains D1Mco4 x 2 and D1Mco4 x 5 had a significantly lower body weight than S, but substrain D1Mco4 x 1 did not (Table 1). Thus in Fig. 3 there might be a body weight QTL in the differential segment between D1Mco4 x 2 and D1Mco4 x 1 (i.e., D1Mgh3 to D1Rat 24).
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DISCUSSION
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It was obvious from our previous linkage analysis comparing Dahl S and LEW rats that chr 1 potentially contained multiple blood pressure QTL (12, 15). Linkage analysis for QTL, however, leads one only to large chromosomal regions, especially when multiple QTL are involved. Using congenic strains, we previously localized a blood pressure effect to a 25-cM region (36) referred to here as QTL region 1. In the present work this region was shown to contain at least two QTL referred to as QTL 1a and QTL 1b. In addition a more centromeric QTL was defined here and is referred to as QTL region 2.
Rat chr 1 has been the subject of considerable work both for hypertension and other related phenotypes. Early interest in chr 1 was stimulated by the fact that the Sa gene is on chr 1. The Sa gene was originally described as being expressed more in kidneys of spontaneously hypertensive rats (SHR) than normotensive controls (21). Subsequent analysis using congenic strains showed, however, that the Sa gene was eliminated as a candidate gene for blood pressure both in Dahl S rats (36) and in SHR (18, 40). This is obvious in Fig. 2, where the Sa gene falls outside of the newly defined QTL regions, but it is contained in a strain, Chr1 x 15, that has no effect on blood pressure.
The positions of congenic strains that were made by others (11, 18, 23, 39) and that had an effect on blood pressure are also indicated in Fig. 2. These strains all potentially overlap with QTL 1b (Fig. 2). In addition, Fig. 2 indicates the position of QTL described by linkage analysis in various rat strains that overlap with QTL 1a, QTL 1b, or both. These are as follows: the blood pressure salt-susceptibility (SS1b) locus described by Yagil et al. (48) in a cross of Sabra hypertension-prone and hypertension-resistant rats; the mean arterial pressure locus (MAP-1) and blood-pressure-independent ventricular mass (LVM-2) locus described by Innes et al. (20) in a cross of SHR and Donryu rats; a renal failure (RF-2) locus described by Brown et al. (5) in a cross of the fawn-hooded rat and the ACI strain; and a locus (STR1) described by Rubattu et al. (35) affecting the latency of stroke development in a cross of stroke-prone SHR and stroke-resistant SHR. Thus there is an impressive overlap of our blood pressure QTL region 1 with QTL for phenotypes that all could conceivably have the same genetic basis.
The blood pressure QTL region 2 defined in Fig. 3 also overlaps with a second salt-susceptibility (SS1a) locus described by Yagil et al. (48) in Sabra rats by linkage analysis. Superficially there is, therefore, very good correspondence between the regions identified in Dahl and Sabra rats for blood pressure QTL. In both models, salt susceptibility/resistance is an important component of the blood pressure response.
Equally interesting are the QTL phenotypes that are outside of our blood pressure QTL regions as defined in the S vs. LEW comparison. Thus renal failure locus 1, RF1, which is the main locus for renal failure in the fawn-hooded rat (5), is at the very lower part of the linkage map in Fig. 1 around D1Mgh12. A QTL for differences in renal hemodynamics appears to be located in the same general region (22).
Interactions among blood pressure QTL are common in our experience. Such interactions are seen either as genetic background effects (6, 7, 34) or as a significant interaction between specific pairs of loci in a factorial analysis of variance in segregating populations (2, 9, 12). The data in Fig. 2 suggest that the blood pressure effects of QTL 1a and QTL 1b are not additive (i.e., they interact). QTL 1a has a blood pressure effect of -35 mmHg, i.e., the effect of strain (Chr1 x 3) x 14. QTL 1b has an effect of about -24 mmHg, i.e., the average of the effects of strains (Chr1 x 3) x 2 and (Chr1 x 3) x 3. If these effects were additive, then a strain that included both QTL would be expected to influence blood pressure about -59 mmHg. The strains Chr1 x 3 and (Chr1 x 3) x 6 both include QTL 1a and QTL 1b, and their blood pressure effects are -39 and -31 mmHg, respectively, for an average blood pressure effect of only -35 mmHg, compared with the -59 mmHg expected. Such an interaction is only suggestive at this point, because to prove it we feel it is mandatory to study the strains involved concomitantly in an experiment specifically designed to test the interaction. This was done, for example, using congenic and double congenic strains to establish an interaction between blood pressure QTL on chr 2 and chr 10 (33).
Using the data in public databases and published comparative maps (see MATERIALS AND METHODS), we determined the relationships of our rat chr 1 blood pressure QTL to the rat cytogenetic map and to syntenic regions of the mouse and human. These summaries are given in Figs. 4 and 5 for QTL region 1 and in Figs. 6 and Fig. 7 for QTL region 2. Supplementary Table 2 gives the gene symbols and names for all the known genes on the comparative maps in the regions of interest. (Please refer to the Supplementary Material1 for this article, published online at the Physiological Genomics web site.)

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Fig. 4. Comparison of the location of the blood pressure QTL 1a and QTL 1b, defined on the linkage map, to the cytogenetic and radiation hybrid maps. Known genes are shown in parentheses, and their full names are given in Supplementary Table 2 (published online at the Physiological Genomics web site). See MATERIALS AND METHODS for construction of the cytogenetic and radiation hybrid maps from public databases.
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Fig. 5. Comparative mapping of blood pressure QTL 1a and QTL 1b from the rat radiation hybrid map to syntenic regions of mouse and human chromosomes. If the exact location of a rat gene to a specific cytogenetic band on chr 1 was not available, then its assignment to chr 1 was indicated in parentheses. The cytogenetic map positions for human genes are given in parentheses. Mouse gene positions are given (in cM) in parentheses. See MATERIALS AND METHODS for construction of these maps from public databases.
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Fig. 6. Comparison of the location of the blood pressure QTL region 2 defined on the linkage map to the cytogenetic and radiation hybrid maps. Known genes are shown in parentheses and are given in Supplementary Table 2 (published online at the Physiological Genomics web site).
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Fig. 7. Comparative mapping of the blood pressure QTL region 2 from the rat radiation hybrid map to syntenic regions of mouse and human chromosomes. The format is the same as in Fig. 5.
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The only striking candidate in our QTL regions is the Slc9a3 gene encoding the Na+/H+ exchanger 3, which is in QTL region 2. There is an extensive literature at the physiological level relating Na+/H+ exchange to hypertension in both animals (4) and humans (19). Mice homozygous for targeted disruption of the Slc9a3 gene show mild diarrhea, an intestinal absorption defect, mild acidosis, impaired bicarbonate and fluid absorption in the renal proximal convoluted tubules, and reduced blood pressure (38). Gene disruption experiments, of course, do not prove that naturally occurring variation in Slc9a3 causes changes in blood pressure. Also the QTL region 2 is still quite large (17 cM) and could contain many unknown candidate genes.
QTL region 2 also has some overlap with blood pressure QTL described in the mouse and man. Wright et al. (46) performed genome scans in crosses involving Schlager mice (37). One of their QTL was on mouse chr 10 between positions 4 cM and 48 cM, which overlaps significantly with our QTL region 2 as seen in Fig. 7. Wright et al. (46) also described a blood pressure QTL on mouse chr 13 between positions 10 cM and 36 cM which does not correspond to the region of mouse chr 13 syntenic to our rat QTL region 2 in Fig. 7.
Our rat QTL region 2 is also syntenic to parts of human chr 5 and chr 6 (Fig. 7). In a genome scan in humans using a discordant full-sibling design, Krushkal et al. (25) described blood pressure QTL in human chromosomal regions 5q33.3 to 5q34 and 6q23.1 to 6q24.1. Figure 7 shows that the human 6q23.1 to 6q24.1 segment overlaps with both the mouse chr 10 blood pressure QTL region noted above and our rat chr 1 QTL region 2. Figure 7 also shows that the region of human chr 5 syntenic to a part of rat QTL region 2 does not correspond to the human QTL region 5q33.3 to 5q34. Thus there is an apparent correspondence between the three species in the approximate location of a blood pressure QTL corresponding to rat chr 1 QTL region 2, the mouse chr 10 QTL between 4 cM and 48 cM, and the human QTL at 6q23.1 to 6q24.1.
The human linkage study of Krushkal et al. (25) also described a blood pressure QTL on human chr 15 between 15q25.1 and 15q26.1. Xu et al. (47) also found a blood pressure QTL on human chr 15 by a sibling-pair paradigm, and this overlaps with the region of Krushkal et al. (25). As can be seen in Fig. 5, this region (human 15q25.1 to 15q26.1) corresponds approximately with our rat blood pressure QTL 1b. There is no QTL described for the mouse syntenic region on mouse chr 7 as given in Fig. 5.
In summary, of the comparative data, there is some correspondence between human and rodent blood pressure QTL locations. It is worth emphasizing, however, that because the regions involved are large and mapping data may not always be accurate, the alignment of QTL among species is not very precise. Also noteworthy is the fact that there is very little correspondence between the blood pressure QTL found by sibling-pair analysis by Krushkal et al. (25) and Xu et al. (47), except in human chr 15. This might be due to the different populations studied, which were in Rochester, MN, and the Yangtze River region of China, respectively.
Finally it is noted that our initial linkage analysis (12) using the MAPMAKER/QTL program (26, 29) yielded three peaks in the LOD plot for rat chr 1. The major peak was actually between our presently defined QTL regions 1 and 2. Thus this peak represents a ghost-peak artifact. This phenomena has been described in simulations of QTL analysis where two linked QTL exist 40 cM or more apart with both plus alleles on the same chromosome (and the contrasting minus alleles of course on the other chromosome) (16, 30, 45).
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ACKNOWLEDGMENTS
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This work was supported by grants to J. Rapp from the National Institutes of Health and by the Helen and Harold McMaster Endowed Chair in Biochemistry and Molecular Biology.
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FOOTNOTES
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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).
1 Supplementary Material (Table 2) to this article is available online at http://physiolgenomics.physiology.org/cgi/content/full/4/3/201/DC1. 
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