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Hypertension. 1999;34:625-630

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(Hypertension. 1999;34:625-630.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Genome Scan for Blood Pressure Loci in Mice

Fred A. Wright; Daniel T. O'Connor; Elizabeth Roberts; Greg Kutey; Charles C. Berry; Lisa U. Yoneda; David Timberlake; Gunther Schlager

From the Division of Human Cancer Genetics and the Comprehensive Cancer Center (F.A.W.), Ohio State University, Columbus, Ohio; the Department of Medicine and Center for Molecular Genetics (D.T.O., L.U.Y.), University of California and VA Healthcare System, San Diego; the Howard Hughes Medical Institute (E.R.), Division of Cellular and Molecular Medicine, University of California, San Diego; the Genetics Program (G.K., G.S.), University of Kansas, Lawrence; and the Department of Family and Preventive Medicine (C.C.B., D.T.), University of California, San Diego.

Correspondence to Fred A. Wright, PhD, Assistant Professor, Division of Human Cancer Genetics, The Ohio State University, 420 W 12th Ave, Room 464A, Columbus, OH 43210. E-mail wright-4{at}medctr.osu.edu


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Abstract—Hypertension is a complex trait of unknown cause in humans. Mice of the inbred strain BPH/2 serve as a rodent model of human hypertension and display elevated blood pressure compared with the hypotensive strain BPL/1. An F2 intercross of BPH/2 and BPL/1 and 2 backcrosses of BPL/1 with Mus spretus were used to perform interval linkage mapping for systolic blood pressure in a genome scan. Significant linkage was observed in the F2s on chromosome 10 (logarithm of the odds score [LOD]=4.9) and on chromosome 13 in the M spretus backcross (LOD=3.3), with additional suggestive LODs on chromosomes 2, 6, 8, and 18. In addition, several suggestive linkages were observed for phenotypes associated with human hypertension. Our study is the first reported genome-wide linkage scan for blood pressure genes in the mouse.


Key Words: linkage • hypertension, genetic • mice • genes


*    Introduction
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 *Introduction
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 down arrowResults
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Hypertension in humans is a prevalent and major predisposing factor to a host of illnesses, including cardiovascular disease, renal impairment, and stroke.1 Although dietary and lifestyle factors have been associated with hypertension,2 3 heredity also plays a strong role,4 and essential hypertension appears to be a complex polygenic trait.5 6 Several candidate genes have been investigated in humans,7 8 9 and blood pressure linkages have been observed in isolated hereditary syndromes.10 11 12 However, with heritability estimates in the range of 25% to 50%,4 a substantial portion of the genetic variation in blood pressure remains unexplained.13 14

Rodent models provide another approach, in which genetic synteny or homology15 may be used to elucidate genetic mechanisms in human hypertension.16 Crosses of the spontaneously hypertensive rat (SHR)17 with normotensive strains and recombinant inbred analyses have provided evidence for blood pressure involvement of several chromosomal regions.6 18 19 Congenic strains have recently provided more definitive evidence in several chromosomal regions by introgressing segments from hypertensive rat strains into a normotensive background.20 21 22 23 Unfortunately, positional cloning strategies in animal models of human hypertension have thus far yielded definitive characterization of few if any loci.24 25

In contrast, few linkage analyses26 have been reported for blood pressure in the mouse, perhaps because of its small size and the difficulty in assessing the phenotype.27 However, when properly performed, noninvasive tail-cuff systolic blood pressure measurements are closely correlated with intra-arterial measurements.28 29 The genetic analysis of newly identified candidate genes in the mouse may provide independent and corroborative evidence of the genetic components of rodent hypertension. Mice of the inbred hypertensive strain BPH/2 and hypotensive strain BPL/1 have been described,27 with comparison of blood pressures and related phenotypes.30 These strains were developed by 2-way selection31 (high blood pressure versus low blood pressure) from an initial cross of 8 inbred strains,27 and inbreeding of the unselected control population resulted in an additional, normotensive strain BPN/3. By use of these strains and a standard biometric method for estimating the minimum number of involved quantitative trait loci (QTLs),32 3 to 5 major genes were estimated to contribute to the 55 mm Hg strain difference in blood pressure, with heritability of 30% to 60%.33 Interestingly, the BPH/2 strain also exhibits elevated pulse rate, left ventricular mass, and hematocrit (percent) compared with BPL/1,27 30 phenotypes that have also been associated with human hypertension and its cardiovascular sequelae.1 34 35 A previous report36 examined cosegregation of blood pressure with 2 candidate genes on chromosomes 8 and 12 in the BPH/2xBPH/1 intercross.

Although the BPH/2 and BPL/1 strains are well described, their genetic similarity and the possibility of random common gene fixation may limit the number of blood pressure genes that vary across the strains. Inbred Mus spretus have relatively high blood pressure, and interspecific crosses of this species with BPL/1 may elucidate additional genes that contribute to variation in blood pressure.37

We undertook a genome-wide QTL linkage scan38 for systolic blood pressure in intraspecific F2 crosses of 247 BPH/2xBPL/1 mice, 92 interspecific backcross (BC) mice designated BCBPL (M spretusxBPL/1)xBPL/1, and 84 interspecific backcross mice designated BCMS (M spretusxBPL/1)xM spretus. Blood pressure was determined from tail-cuff measurements, with multiple observations averaged for each mouse. A microsatellite map39 was used to cover the genome with 91 markers in the F2s and 95 markers in the backcrosses, at an average spacing of {approx}16 cM. Additional phenotypes associated with mouse and human hypertension were also examined for linkage as available.


*    Methods
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 *Methods
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Intercrosses
The BPH/2 and BPL/1 strains have been described30 31 33 ; they were produced from 23 generations of 2-way blood pressure selection followed by >20 generations of brother-sister inbreeding. The 2 inbred strains were mated reciprocally to produce an F1 generation. From the 2 matings using BPH/2 females, 5 brother-sister matings produced 68 F2s. From the 3 matings using BPL/1 females, 7 brother-sister matings produced 98 F2s. Of these 166 mice, 149 produced DNA of sufficient quality for genotyping (77 males, 72 females). These mice are designated "set A." In addition, 98 F2 mice with extreme blood pressures were selected for genotyping from previous sets of 221 F2s as a means of improving power to detect linkage. Of these mice, 49 were selected from the lowest quartile of blood pressure (26 males, 23 females) and 49 from the highest quartile (23 males, 26 females). These extreme mice are designated "set B." Thus, the total number of genotyped F2 mice was 149+98=247. In addition, the phenotypes of the remaining 123 nonextreme mice from the set of 221 F2s were used to provide valid likelihood estimates as described below.

Blood Pressure Measurement
Systolic blood pressures of the mice in set A were measured during the summer of 1994 beginning when the mice reached 100 days old. These determinations were tail-cuff measurements (8-mm ID, 15 mm long) taken on unanesthetized restrained mice with the Narco-Biosystems Physiograph. Five determinations were made on each of 3 days at approximately weekly intervals and then measured once or twice again when the mice were 7 to 8 months old. The blood pressures of the mice in set B were determined in fall and winter of 1992 on the same schedule, when the mice reached 100 days old, at 3 weekly intervals for a total of 15 measurements. All the mice were first trained to tolerate restraint and mild warming (37.5°C) by being placed into the restrainer for 1, 2, and 3 minutes on consecutive days. Most mice had blood pressure measurements on day 4. Some mice required additional training before blood pressures could be determined. The multiple observations for each mouse were averaged to produce a single phenotype value. Because blood pressure in mice varies seasonally and the F2 crosses were measured over different seasons, all blood pressures were converted to deviations from the mean (in mm Hg) within each cross for males and females separately.

Interspecific Backcrosses
Inbred male M spretus were purchased from the Jackson Laboratory, Bar Harbor, Me, and crossed with BPL/1 females to produce an F1. The F1 females were in turn crossed to the BPL/1 males and M spretus males to produce 2 backcross generations: BCBPL and BCMS, respectively. In total, 51 male and 41 female BCBPLs and 38 male and 46 female BCMS mice were produced, for which blood pressures were determined and DNA extracted.

Blood Pressure Measurement
The mice backcrossed to the BPL/1 could have their blood pressures taken in the usual manner as described above, restrained and unanesthetized, after considerable training. Five blood pressure measurements were taken on each mouse on each of 5 or 6 weekly intervals during the fall and winter of 1992/1993 when the mice were 120 to 150 days old. These values were averaged to form a single phenotype value for each mouse.

The mice backcrossed to M spretus were relatively "wild" and could not be trained to tolerate restraint. The blood pressure of these mice was measured under metofane anesthetic when the mice were 5 to 8 months old during a 2-year period, 1993 to 1994. The mice were anesthetized for 2 minutes in a glass jar containing cotton soaked with metofane. The mice were then placed on a warming plate (37.5°C) with a nose cone containing cotton and metofane. Within a few minutes, pulse was discernible in the tail, at which time the nose cone was removed. The measurement of blood pressure commenced and was continued at 1-minute intervals until the mouse regained semiconsciousness. As many as 20 blood pressure measurements were taken on some mice. The last few measurements before the mice regained consciousness were likely to be the most comparable across mice, and these were averaged for each mouse to produce a single phenotype for linkage analysis. All procedures used in the crosses were in accordance with guidelines of the University of Kansas.

Additional Phenotypes
The procedures for determining pulse rate, left ventricular mass, and hematocrit percent are described in more detail elsewhere.30 Pulse rate was measured each time blood pressure was determined. The F2 mice in set A were anesthetized and killed at 150 days old by cervical dislocation. The heart was removed and cleaned and the left ventricle separated and weighed on a Mettler balance.

DNA Preparation and Genotyping
A simple 3-step DNA extraction was performed from mouse tail tissue by use of a Qiagen kit and column (proteinase K step, RNAse A step, and QIAamp spun column; Qiagen Inc). By this procedure, we routinely obtained 160 µg of DNA/tail in 400 µL of Tris-EDTA buffer. Samples were sent to the J.L. Weber laboratory for genotyping.

Markers were scored by at least 2 independent reviewers. In addition, genotypes were reexamined in regions of significant linkage. Markers were spaced as evenly as possible and extended to within 15 cM of both chromosome ends for all but the X chromosome. The mean±SD for marker interval widths was 16.1±7.1 cM for the F2 intercrosses and 16.2±5.1 cM for the backcrosses. Attempts were made to close any gaps >30 cM, but 3 such chromosomal regions for the F2s and 1 region for the interspecific backcrosses remained uninformative at all microsatellites examined.

Linkage and Statistical Analyses
Linkage analysis was performed for each of the 3 crosses with the Mapmaker/QTL program 1.1 (Whitehead Institute)40 on a UNIX workstation. The precise phenotype for each cross was chosen before analysis. Statistical power calculations for a genome-wide scan were performed by use of both simulation and analytic approximations,41 which were in close agreement. The F2 intercross data were shown to have >80% power to detect QTLs contributing 10% of the variation in blood pressure, whereas the backcrosses BCBPL and BCMS had power of 73% and 70%, respectively, to detect loci contributing 20% of the phenotype variation. The crosses were expected to provide little power to detect epistatic interactions among the loci. Mapmaker/QTL allows the inclusion of covariates in the linkage analysis,40 and sex was introduced as an additive effect to reduce error variation.40 42 The covariate also appears in the denominator of the likelihood ratio and thus does not inflate the type I error. Statistical power for the F2s was enhanced by genotyping of the 98 phenotypically extreme (for blood pressure) mice of set B,38 with the phenotypes of the remaining 123 nongenotyped mice also entered to provide valid likelihood estimates and combined with the mice of set A. Pulse rate was analyzed for the F2s in the same manner. The mice in the remaining crosses were not chosen on the basis of extreme phenotype, and all available individuals were used in the analysis.

Linkage analyses used Haldane's map function and marker map locations reported by Research Genetics, which agrees well with other published maps.39 Additional marker ordering and mapping was performed on the data by use of Mapmaker/EXE.43 Maps of mammalian homology reported by the Jackson Laboratory (http://www.informatics.jax.org) were used to compare syntenic regions. Linkage results are reported according to published conservative standards44 for the maximum LOD in a dense genome scan. LODs of 4.3 and 3.3 are considered significant at the 0.05 level for F2 and backcross populations, respectively. Thresholds of 2.8 and 2.3 are considered "suggestive," in that they are expected to occur approximately once in a full genome scan. To facilitate communication,44 all regions with LODs >2.0 are reported here.

Additional Statistical Analyses
Additional statistical analyses were performed with the S-Plus 3.4 statistics package (MathSoft, Inc). A {chi}2 contingency table test of Mendelian ratios revealed a statistically significant imbalance in parental strain origin of allele marker D13 Mit78 in the F2 cross, in a region not showing evidence of blood pressure linkage. Linkage results were also confirmed by interval mapping regression45 and permutation-based tests of linkage significance.46 ANOVA tests of 2-way genetic interactions of all pairs of markers were also performed, with permutation tests used to construct a genome-wide P value.


*    Results
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 *Results
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Blood Pressure
Systolic blood pressure measurements in the F2 intercrosses and BCBPL mice were performed with tail cuffs on conscious, restrained mice; the BCMS mice were measured while regaining consciousness from metofane anesthetic. The measurement procedures varied (see Methods) according to the restraint and anesthetic procedures necessary for each cross. The systolic blood pressures in males were as follows (mm Hg, mean±SD): 111.7±11.4 in the F2 intercross, 95.2±12.5 in the BCBPL backcross, and 94.0±34.5 in the BCMS backcross. Blood pressures in females were 110.5±13.8 in the F2 intercross, 91.9±9.3 in the BCBPL backcross, and 100.1±37.9 in the BCMS backcross. The larger variances in the BCMS cross may reflect the influence of the anesthetic.

Interval mapping was performed with Mapmaker/QTL40 for each of the 3 crosses and revealed 10 regions with LOD scores >2.0 (Table 1). Two regions provided significant linkage evidence according to conservative standards44 : the interval D10 Mit123–D10 Mit117 (LOD=4.9) in the F2 intercross and D13 Mit198 (LOD=3.3) in the BCBPL backcross. Additional suggestive loci were identified on chromosomes 2, 6, 8, and 18, including a region, D2 Mit192/274, that approached significant linkage in the BCBPL backcross with LOD=3.2. A moderate amount of phenotype variation (10% to 25%) may be attributed to these loci individually, and the summed contribution of the suggestive or significant loci (between 30% and 50% in each cross) is consistent with previous heritability estimates.33 The Figure plots the LOD scores for blood pressure on the 4 chromosomes that achieved suggestive or significant linkage.


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  		Table 1. Regions With LODs >2.0 for Blood Pressure and Related Phenotypes



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  		Figure 1. LOD scores for blood pressure in 247 F2 progeny (BPH/2xBPL/1, bold line), 92 backcross progeny, designated BCBPL [(M spretusxBPL/1)xBPL/1, thin line], and 84 backcross progeny, designated BCMS [(M spretusxBPL/1)xM spretus, dotted line]. Intercross markers appear on the bottom horizontal axis, backcross markers on the top axis.

BPL/1 alleles are present in all the crosses, and QTL alleles from this strain would be expected to reduce blood pressure relative to any other parent strain. Although this is true for most of the regions identified, the BPL/1 allele near D13 Mit198 appears to increase blood pressure relative to M spretus. A similar phenomenon has been reported in the rat,47 in which alleles at some loci from the SHR strain appeared to decrease blood pressure. There was no evidence of chromosome 13 involvement in the BCMS cross, suggesting that the BPL/1 allele may be dominant or due to differing genetic background between the strains (ie, other interacting loci).

The LOD score analysis for the significant loci was supported by additional statistical procedures.45 46 However, the LOD score of 4.9 was achieved only in a relatively large interval between markers (although an LOD >3.0 was observed at flanking marker D10 Mit123). Interestingly, the locus on chromosome 10 does not show evidence in either of the interspecific backcrosses, suggesting that M spretus may not have an allele conferring high blood pressure in this region.

Multiple Gene Models
Additive models38 with multiple genes were explored with Mapmaker/QTL, but no new loci were identified beyond those listed in Table 1. Using ANOVA with interaction terms,48 we examined all pairs of markers for evidence of epistatic effects on blood pressure. None of these interaction effects were statistically significant when permutation testing was used to apply a multiple-comparison adjustment.

Comparison of Blood Pressures Across Strains
Measurements performed under inhaled metofane anesthetic provide a uniform condition under which blood pressures can be compared across strains and crosses. All of the BCMS mice in this report were measured under metofane anesthetic (see Methods). A few mice from the other strains were chosen to be measured under metofane anesthetic (in addition to their unanesthetized measurements) and are presented for comparison in Table 2. This table exhibits the anticipated differences across strains, with the exception of the BCMS cross. The average blood pressure for BCMS females was greater than that of both of the parent strains (not significant). Metofane phenotypes for F1 females were unavailable.


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  		Table 2. Systolic Blood Pressures (mm Hg) in Several Mouse Crosses Under Metofane Inhalation Anesthetic1

Additional Phenotypes
In addition to blood pressure, the phenotypes pulse rate, relative left ventricular mass (left ventricular mass/body mass), and hematocrit (percent) were examined. Pulse rate was measured concurrently with blood pressure. Left ventricular mass was measured in {approx}50% of the F2 mice (n=126) when they were killed at 180 to 250 days old, and hematocrit (percent) was measured only in males of this group (n=71). The procedures for obtaining these phenotypes are discussed in greater detail elsewhere.30 The linkage results are given in Table 1. None of the regions showed significant linkage, although a LOD of 4.2 for pulse rate was highly suggestive for a locus in the interval D3 Mit60/22 among the F2s.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
Hypertension is a complex trait49 with multiple genetic and environmental determinants.50 We demonstrated that several regions of the mouse genome show significant or suggestive cosegregation with systolic blood pressure, and these apparent loci vary across the 3 experimental crosses examined (Table 1). A LOD score of 4.9 was observed on chromosome 10 in an F2 intercross and a LOD of 3.3 on chromosome 13 in an interspecific N2 backcross, surpassing rigorous standards44 for establishing linkage. The comparatively large interval between the markers flanking the area of peak LOD score=4.9 (Table 1; Figure) on chromosome 10 in the F2 cross has thus far resisted attempts to identify further microsatellite polymorphisms distinguishing the parental strains (BPL/1 and BPH/2) in this region; nonetheless, the presence of a LOD >3.0 at flanking marker D10 Mit123 supports linkage in the region.

Other suggestive44 blood pressure linkages were found on chromosomes 2, 6, 8, and 18. Interestingly, only chromosome 2 shows evidence of involvement in multiple crosses (Table 1 and Figure), and 1-LOD-unit support intervals in the 2 backcrosses exhibit some overlap. The overall results are consistent with the complex, polygenic nature of blood pressure.51

Loci encoding components of the renin-angiotensin system are leading candidate genes for hypertension, and affected sib-pair methods have found evidence for linkage of the angiotensinogen (AGT) locus to human hypertension.52 Some alleles at the angiotensin II receptor type I locus (AGTR1) are associated with human hypertension,53 and alleles at the angiotensin-converting enzyme (ACE) locus are associated with adverse myocardial events in hypertension.54

In the spontaneously hypertensive rat, linkage established the role of a major locus (BPH1) near ACE on rat chromosome 1055 56 ; the mouse homologue is probably on chromosome 11. In the mouse, renin-angiotensin components include Agt at 68 cM (angiotensinogen, renin substrate) on mouse chromosome 8, Ren (renin) on mouse chromosome 1 at 70 cM, angiotensin-converting enzyme mouse homologue Ace not assigned but probably on chromosome 11 by synteny, and Agtr2 (angiotensin II receptor type II) on the mouse X chromosome. None of these regions displayed significant linkage to blood pressure in our data. In the mouse genome, there are 2 angiotensin II receptor type I loci57 : Agtr1a, at 16 cM on mouse chromosome 13, and Agtr1b, at 2 cM on mouse chromosome 3. Mouse chromosome 13 showed significant linkage to blood pressure in the BCBPL (backcross to BPL/1; Table 1 and Figure), with the support interval containing Agtr1a.

These syntenic comparisons do not provide support for mouse homologues to the candidate regions in humans and rat models. However, to aid future comparisons, we list in Table 1 the presumed homologous regions in the human and rat genomes to the mouse loci identified in this study. The resolution of syntenic maps varies according to region, and in many cases, the mouse blood pressure locus is not well localized, so the syntenic region may include multiple chromosomal regions in the comparison organism.

In conclusion, this study is the first reported genome-wide linkage scan for blood pressure genes in the mouse. Linked regions of mouse-human chromosomal synteny may suggest novel loci that influence blood pressure in humans. As the genetic maps of mammals improve, investigators can increasingly take a positional candidate approach, testing logical candidate genes in linked regions.


*    Acknowledgments
 
This study was supported in part by a grant from the American Heart Association Kansas Affiliate (University of Kansas) (G.S.), NIH grants GM-58934 and P30CA-16058 (F.A.W.), and a grant from the Department of Veterans Affairs (D.T.O.). Genotyping was provided by a grant from the NHLBI Mammalian Genotyping Service directed by J.L. Weber. Xin Gao and Renée Mackey provided technical assistance. Two anonymous reviewers provided valuable advice.

Received March 2, 1999; first decision March 29, 1999; accepted June 3, 1999.


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