Severe hypertension caused by alleles from normotensive Lewis for a quantitative trait locus on chromosome 2
Vasiliki Eliopoulos1,
Julie Dutil1,
Yishu Deng2,
Myrian Grondin1 and
Alan Y. Deng1
1 Research Centre-Centre Hospitalier de l'Université de Montréal (CHUM), Hôtel Dieu, Montreal, Quebec, Canada
2 Third People's Hospital of Yunann, Kunming, Yunnan, China
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ABSTRACT
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Pursuing fully a suggestion from linkage analysis that there might be a quantitative trait locus (QTL) for blood pressure (BP) in a chromosome (Chr) 2 region of the Dahl salt-sensitive rat (DSS), four congenic strains were made by replacing various fragments of DSS Chr 2 with those of Lewis (LEW). Consequently, a BP QTL was localized to a segment of around 3 cM or near 3 Mb on Chr 2 by comparative congenics. The BP-augmenting alleles of this QTL originated from the LEW rat, a normotensive strain compared with DSS. The dissection of a QTL with such a paradoxical effect illustrated the power of congenics in unearthing a gene hidden in the context of the whole animal system, presumably by interactions with other genes. The locus for the angiotensin II receptor AT-1B (Agtr1b) is not supported as a candidate gene for the QTL because a congenic strain harboring it did not have an effect on BP. There are
19 known and unknown genes present in the QTL interval. Among them, no standout candidate genes are reputed to affect BP. Thus the QTL will likely represent a novel gene for BP regulation.
comparative congenics; functional genomics; blood pressure; fine mapping
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INTRODUCTION
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OUR INITIAL LINKAGE STUDIES indicated that a blood pressure (BP) quantitative trait locus (QTL) was probably present in a segment between D2Mit6 and D2Mco19 markers based on an F2 [Dahl salt-sensitive (DSS) x Lewis (LEW)] population (16). The detection of this QTL was supported by a maximum LOD score of 2.9 (16) and, therefore, was still below what was considered the highly significant level for detecting a QTL in such a population (20). An obvious question to pose is, "Could this detection be a true localization of a BP QTL?" This issue is important because linkage analysis is usually the first step in localizing a QTL for complex traits on chromosome (Chr) 2 (3, 6, 911, 25, 27, 28, 31). Moreover, Stoll et al. (30) detected QTLs for several physiological phenotypes in the vicinity of the BP QTL on Chr 2 found in our F2(DSS x LEW) population (16). This region, therefore, could potentially harbor important genes not only for BP, but also for other physiological traits.
On the basis of the above considerations, there were several questions to be addressed. 1) Did a BP QTL exist in a region detected by linkage analysis (16)? 2) If it did, does LEW possess BP-raising alleles, and can the gene encoding the angiotensin receptor type AT-1B (Agtr1b) be supported as a candidate gene for the QTL? The present investigation was intended to address these two questions and to fine map the QTL in question.
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MATERIALS AND METHODS
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Animals and generation of congenic strains.
Protocols for handling as well as maintaining animals were approved by our institutional animal committee (CIPA). All experimental procedures were in accordance with the guidelines of institutional, provincial, and federal regulations. The breeding procedure, markers used in genomic scans, and screening protocol for generating congenic strains were essentially the same as reported previously for mapping BP QTLs on other chromosomes (2, 7, 2124, 29). For our current work, four congenic strains were produced and are designated as DSS.LEW-(D2Rat199-D2Rat143)/Lt (abbreviated as C2S.L1), DSS.LEW-(D2Rat18-D2Chm277)/Lt (C2S.L2), DSS.LEW-(Prlr-D2Rat143)/Lt (C2S.L3), and DSS.LEW-(D2Rat199-D2Mco17)/Lt (C2S.L4), respectively. C2 indicates that the strain is made for Chr 2. The chromosome regions homozygous LL in the congenic strains are shown as solid bars in Fig. 1. All the markers in the region concerned were genotyped in the congenic strains.

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Fig. 1. Fine mapping of C2QTL4. The linkage map is essentially the same as that published previously, which is a composite map of Chr 2 (8). Solid bars under congenic strains symbolize the Dahl salt-sensitive (DSS) chromosome fragments that have been replaced by those of the Lewis (LEW) rat. The entire region indicated by solid bars and junctions between the solid and open bars are homozygous for LEW, i.e., LL, on the map for all the markers listed in the corresponding positions. Open bars on ends of solid bars indicate the ambiguities of crossover break points between markers. Agtr1b, angiotensin receptor type AT-1B; Prlr, prolactin receptor. The rest of the markers are anonymous. Primers for the new D2Chm markers are as follows: D2Chm145 (forward 5'-ggggagagtttcaaccctactt-3', reverse 5'-ggacccaatcggctcttaat-3'), D2Chm149 (forward 5'-ttctgccttagtccccagtc-3', reverse 5'-cctgcctaatttgcttttgg-3'), D2Chm172 (forward 5'-gtggccagggactgagaata-3', reverse 5'-cgtgaagagagggaacctca-3'), D2Chm175 (forward 5'-ccagccactttgctgaagtt-3', reverse 5'-ccccagctctggtaaacact-3'), D2Chm191 (forward 5'-tttccatgaatcctggcagt-3', reverse-5' aaagccacatgccaattctc-3'), D2Chm192 (forward 5'-acagcagacattcgcaagc-3', reverse 5'-agcagacacaaccctgagt-3'), D2Chm 229 (forward 5'-aaagctgccacgaacaatct-3', reverse 5'-tggacctaagtcccaaagga-3'); D2Chm233 (forward 5'-tgggtcccacctctagacac-3', reverse 5'-ggccactttgtgctggataa-3'), D3Chm238 (forward 5'-ggatagccagggctacataga-3', reverse 5'-cccatagggcccaatagttc-3'), D2Chm277 (forward 5'-tcactggctcaaaagcctct-3', reverse 5'-ggttgtaagttagaatactccccatc-3'), D2Chm278 (forward 5'-tctctgtctctgcccctacc-3', reverse 5'-ctccaaaagagccgagtgtc-3'), D2Chm280 (forward 5'-ccatagaaagatcacccttgc-3', reverse 5'-tgggttcttactgacaaagatgc-3'), D2Chm289 (forward 5'-cagcagaaatgcttgcctaa-3', reverse 5'-tgacaagcaggaatagcctct-3'), D2Chm294 (forward 5'-ggcagaggcaggtgaatcta-3', reverse 5'-tcacagagactatggcagactga-3'), D2Chm296 (forward 5'-tgtgcagccatggtacaaat-3', reverse 5'-ccttttcacccttcccaaat-3'), D2Chm299 (forward 5'-accccagactcagcatttga-3', reverse 5'-tcaaactaccccatcaggattc-3'). Congenic strains were as follows: DSS.LEW-(D2Rat199-D2Rat143)/Lt (C2S.L1), DSS.LEW-(D2Rat18-D2Chm277)/Lt (C2S.L2), DSS.LEW-(Prlr-D2Rat143)/Lt (C2S.L3), and DSS.LEW-(D2Rat199-D2Mco17)/Lt (C2S.L4), respectively. MAP, averaged mean arterial pressure during the period of measurement for each strain; QTL, quantitative trait locus; Chr, chromosome. ANOVA with the Dunnett's correction compares MAPs between DSS and each of the congenic strains. The placement of C2QTL4 is to the right of congenic strains. Heart rates of the strains are 355 ± 13 (LEW), 417 ± 5 (DSS), 443 ± 4 (C2S.L1), 426 ± 5 (C2S.L2), 426 ± 14 (C2S.L3), and 427 ± 5 (C2S.L4) beats/min, respectively. Supercontigs were those taken from a database search at http://www.ncbi.nlm.nih.gov/mapview/. Nos. in parentheses below supercontigs represent their sizes in Mb. Genes found in the QTL-residing region of rat Chr 2 and homologous regions on mouse Chr 15 and human CHR 5 are shown at right, based on a database search at http://www.ncbi.nlm.nih.gov/mapview/. They are as follows: Gdnf, glial cell line-derived neurotrophic factor; IDN3, IDN3 protein; IL7R, interlukin-7 receptor; Kpl2, Kpl2 protein; Nup155, nucleoporin 155 kDa; SKP2, S phase kinase-associated protein-2; Slc1a3, solute carrier family 1 member 3. Locs or FLJs refer to possible genes predicted by computer programs.
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Production of new markers.
The process is similar to what was reported previously for other chromosomes (2, 22, 23). The PCR primers for the new D2Chm markers used in the present studies are given in the legend for Fig. 1.
Breeding protocol for BP studies.
The determination of BPs is essentially the same as described previously (2, 7, 12, 13, 2124, 29). In brief, the mating pairs of the DSS and congenic strains to be studied were bred simultaneously. Male rats were selected and weaned at 21 days of age, maintained on a low-salt diet (0.2% NaCl, Harlan Teklad 7034), and then fed a high-salt diet (2% NaCl, Harlan Teklad 94217) starting from 35 days of age until the end of the experiment. Telemetry probes were implanted when rats were 56 days old (i.e., after 3 wk of the high-salt diet), with their body weights between 250 and 320 g. After the surgery, the rats were allowed 10 days to recuperate before their BPs were read. The implantation of telemetry probes and the age and postoperative cares of animal are the same as described before (12, 13).
BP measurements.
The basic protocol was similar to our previous congenic work, regarding the age and sex of the rats and in terms of the time table of dietary treatments (2, 7, 12, 13, 2124, 29). One BP reading was taken every 2 min for the period of measurement. Then, these readings were averaged for 6 h to obtain one data point, which appears as a point on the graph for the purpose of showing diurnal variations (Fig. 2). Please see Dutil and Deng (12) for detailed comparisons in BPs of DSS and a congenic strain exhibiting even finer variations during our typical BP measurements.

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Fig. 2. Comparisons of blood pressures (BPs) between congenic strains and the DSS strain. A and D: systolic arterial pressures (SAPs). B and E: diastolic arterial pressures (DAPs). C and F: mean arterial pressures (MAPs). Each time point on the graph represents an average of 6-h readings. Values are means ± SE; n = no. of rats. For designations of congenic strains, see the legend for Fig. 1.
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Statistical analysis.
Repeated measures ANOVA followed by the Dunnett test in the SYSTAT 9 program (SPSS Sci.; Chicago, IL) was used to compare the significance level for a difference or a lack thereof between a congenic strain and the DSS strain. The Dunnett test takes into account multiple group comparisons as well as sample sizes among the comparing groups. In the analysis, a BP component was compared at each day for the period of measurement among the strains (2, 7, 12, 13, 2124, 29).
Because BPs of rats were measured continuously for
23 wk and varied with time, the numbers given at the bottom of Fig. 1 represent only averaged values of mean arterial pressures for a strain and do not reflect the day-to-day BP variations. A Dunnett value including "<" given in each comparison between congenic and DSS strains was the most conservative P value among all the days of comparisons.
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RESULTS
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Congenic constructions.
A total of eight rats with various crossovers in the regions of interest were obtained. Among them, two rats died before yielding any strains, and six rats eventually gave rise to six congenic strains. Among them, two contained chromosome fragments inside those of C2S.L2 and C2S.L3 (Fig. 1). Because both C2S.L2 and C2S.L3 did not exhibit BP effects (Fig. 2), these two congenic strains were discarded.
The four congenic strains, C2S.L1, C2S.L2, C2S.L3, and C2S.L4 (Fig. 1), were designed to overlap each other in chromosome coverage but, in the meantime, leave no gaps uncovered for the entire region of interest. C2S.L3 was to include the gene Agtr1b for the specific purpose of testing its candidacy for a BP QTL.
BP studies.
All the BP components were measured, including systolic (SAP), diastolic (DAP), and mean arterial pressures (MAP). BPs for all the strains shown in Fig. 1 were measured at least at two different times, i.e., they were separate litters raised at various times during a period of 1 yr. This consideration was designed to minimize the environmental influences on the phenotyping accuracy. The results showed that BPs for each strain, C2S.L1, C2S.L2, C2S.L3, C2S.L4, and DSS, were not different at the separate periods of measurements (data not shown). Therefore, the BP data for each strain were pooled from these reproducible measurements (Fig. 2).
Mapping of a BP QTL by comparative congenics.
SAP, DAP, and MAP of LEW were lower (P < 0.001) than those of DSS (Fig. 2); in contrast, SAPs, DAPs, and MAPs of C2S.L1 and C2S.L4 were higher (P < 0.003) than those of DSS (Fig. 2). In comparison, MAPs, DAPs, and SAPs of C2S.L2 and C2S.L3 were not different (P > 0.12) from those of the DSS strain (Fig. 2). Consequently, the region containing the QTL, C2QTL4, can be localized to the segment that was in common between C2S.L1 and C2S.L4, but not included in C2S.L2 and C2S.L3 (Fig. 1). This segment is between D2Chm277 and Prlr (Fig. 1).
The interval of D2Chm277/Prlr was calculated to be
3 Mb as follows (Fig. 1). D2Chm277 is at the position of 1.9 Mb in supercontig 47,621.1 (with 1.9 Mb total), Prlr is at the position of 2.9 Mb in supercontig 47,622.1. The QTL interval would be 2.9 Mb plus a gap with an unknown number of bases between the two supercontigs. Calculating from the distance of cM 12.7 divided by 13 Mb in physical distance between C2Mco13 and Prlr (Fig. 1), 1 cM = 1 Mb. Thus the C2QTL4 interval of 3 Mb is
3 cM.
Systematic comparative mapping in search of candidate genes.
Possible genes in the QTL interval are included in Fig. 1 by comparative mapping among the rat, mouse, and human genomes at http://www.ncbi.nlm.nih.gov/mapview/. Initial annotations of possible expressions of genes and undefined loci present in the QTL interval were carried out, and results are presented in Table 1. Figure 3 synthesizes the QTL localizations so far documented in the literature, and places the present QTL with reference to the others.
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DISCUSSION
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Major findings of the current work are as follows. 1) LEW carries high-BP alleles and DSS carries low-BP alleles at C2QTL4, despite the fact that LEW is a normotensive strain, whereas DSS is a hypertensive strain. The congenic strain, C2S.L1 and C2S.L4, can be classified as a "DSS" strain with severe hypertension. 2) The position of C2QTL4 has been restricted to an interval of 3 Mb (or
3 cM) by comparative congenics, i.e., comparing the two congenic strains that had with two that did not have BP effects. The QTL interval harbors 19 possible genes, 4 known and 15 undefined loci (Fig. 1). This size is amenable for positional cloning. 3) Agtr1b has been disqualified as C2QTL4 because C2S.L3 had a BP not distinguishable from that of DSS. Because no apparent candidate genes are found in the segment harboring the QTL, the QTL discovery will inevitably lead to the identification of a brand new gene previously unknown to influence BP.
BP of DSS could be raised by substituting alleles of C2QTL4 with those of LEW (Figs. 1 and 2). Although LEW contains C2QTL4 alleles that exert BP-elevating effects, paradoxically, BP of the LEW strain itself is considerably lower than that of DSS (Fig. 2). This fact indicates that it is not a single QTL, but rather it is how this QTL interacts with others that determines the overall BP of a strain. Among the mechanisms of interactions, one can be epistasis. For example, the two QTLs on Chr 3 possessed opposing BP effects, one decreasing and other increasing BP (23). Yet the combined effect of these two QTL was equal to that of the QTL that decreased BP (23). This epistasis implies that these two QTLs acted in the same pathway/cascade leading to BP determination (4, 5). In addition, the numerical advantage of BP-decreasing QTLs might have outweighed and nullified the effect of fewer BP-increasing QTLs in LEW, since there have been more BP-decreasing QTLs found in LEW than in DSS (4).
C2QTL4 is localized to the Chr 2 segment between D2Chm277 and Prlr markers because C2S.L1 and C2S.L4 did, whereas C2S.L2 and C2S.L3 did not, have BP effects (Figs. 1 and 2). This approach of comparative congenics in placing a BP QTL is consistent with our other work in mapping C10QTL2 and C10QTL3 on Chr 10 (24) and in mapping two QTLs in the lower part of Chr 2 (Fig. 3). For example, using the same approach, we initially localized C2QTL1 to a 5.7-cM segment of none overlapping between a congenic strain that had and a congenic strain that did not have a BP effect on Chr 2 (13). Later, a congenic substrain specifically involving the 5.7-cM region proved that, indeed, there was a BP QTL in the region (14). In line with this expectation, an eventual proof that C2QTL4 is present in the fragment shown in Fig. 1 will come from making a congenic strain that specifically involves the interval of D2Chm145/Prlr. A congenic substrain trapping the QTL with a "minimum" chromosome coverage (e.g., 1 cM or less) is desirable not only for the proof of its existence, but also for its final molecular identification.
The possibility of finding more than one QTL in the fragment between D2Chm277 and Prlr (Fig. 1) cannot be excluded. Only further fine congenic mapping can resolve this issue. There is evidence that multiple BP QTLs were present close to each other in the lower part of Chr 2 (1, 12, 13, 18, 19), on Chr 10 (24), on Chr 3 (23), on Chr 8 (2), on Chr 5 (17), and on Chr 1 (15, 26).
It is worth noting that Agtr1b is not supported as a candidate gene for the QTL, because congenic strain C2S.L3 harbors it and yet did not show a BP effect (Figs. 1 and 2). A thorough comparative mapping among the rat, the mouse, and the human genomes did not reveal obvious candidate genes known to influence BP in the interval of D2Chm277 and Prlr containing the QTL (Fig. 1). Thus it is most likely that this QTL will represent a novel gene for BP regulation.
Since our initial work (6, 10, 16), rat Chr 2 has been shown to contain QTLs with BP-raising alleles originating from various hypertensive rat models (1, 3, 19, 25, 28, 31). These QTLs are mostly clustered in the region between D2Rat303 and D2Mgh12 markers in the lower part of the chromosome (Fig. 3). C2QTL4, identified in our current work, seems to be unique in its chromosome location and, in contrast to other BP QTLs, in its BP-decreasing effect from DSS.
The existence of C2QTL4, found by linkage (16) followed by the current congenic confirmation, was in contrast to the statistical detection (6, 9) and subsequent nonconfirmation (13) of another QTL near Agtr1b (9) in a comparison of DSS with the Milan normotensive strain (MNS). The latter outcome could probably be attributed to a false positive of statistics in our linkage results in the F2(DSS x MNS) population (6, 9). Thus it is essential to verify the existence of a QTL by congenic strains after linkage.
As for a possible candidate gene for C2QTL4, a number of genes or undefined loci located in the QTL interval (Fig. 1) are expressed in organs potentially involved in BP homeostasis such as the heart and kidneys (Table 1). On the basis of this information alone, however, it is impossible to draw any functional inferences. Nevertheless, the QTL alleles will contain a significant nucleotide difference(s) in either the coding or regulatory region(s) that will change either the function of the gene product or its level of expression(s). Only a positional clone will accomplish this task.
In conclusion, there is a QTL(s) for which BP-raising alleles originate, paradoxically, from the normotensive LEW strain instead of the hypertensive DSS strain on Chr 2. This QTL can act independently from other QTLs in the context of the DSS background. Genes located in the QTL interval are not known to affect BP. Therefore, the gene discovery on this QTL will unravel novel mechanisms controlling the pathogenesis of hypertension.
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GRANTS
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This work was supported by a grant from the Canadian Institutes for Health Research (CIHR) to A. Y. Deng. A. Y. Deng is an Established Investigator of the American Heart Association, National Center. J. Dutil holds a CIHR Graduate Fellowship.
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ACKNOWLEDGMENTS
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We thank Eric Martel for the computer program used to find microsatellites in the rat genome.
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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: A. Y. Deng, Research Centre-Centre Hospitalier de l'Université de Montréal (CHUM), 7-132 Pavillon Jeanne Mance, 3840, rue St. Urbain, Montréal, Québec, H2W 1T8, Canada (e-mail: alan.deng{at}umontreal.ca)
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