(Circulation. 1995;92:2381-2384.)
© 1995 American Heart Association, Inc.
Articles |
Genetic Linkage of the ACE Gene to Plasma Angiotensin-Converting Enzyme Activity but Not to Blood Pressure
A Quantitative Trait Locus Confers Identical Complex Phenotypes in Human and Rat Hypertension
From the Cardiovascular Division, Department of Medicine, Brigham & Women's Hospital, the Department of Cardiology, Children's Hospital, Harvard Medical School, and the Division on Biological Sciences, Harvard School of Public Health, Boston, Mass (R.K., N.H., K.L.); and the Max Delbrück Centre for Molecular Medicine (D.G.), Berlin, Germany.
Correspondence to Klaus Lindpaintner, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Thorn 1103, Boston, MA 02115. E-mail kl@calvin.bwh.harvard.edu.
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Abstract |
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Background An allelic variant of the ACE gene has been found to be linked to plasma angiotensin-converting enzyme (ACE) activity in humans and has been implicated in the etiology of some common cardiovascular disorders. Previously, we have shown significant genetic linkage of blood pressure to a region on rat chromosome 10 that contains ACE in an experimental F2-intercross between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and the normotensive Wistar-Kyoto (WKYHD-0) reference strain. Subsequent investigations revealed marked differences in plasma ACE activity among the SHRSPHD and WKYHD-0 strains. Nonetheless, the physiological relevance of these findings remained obscure. We therefore investigated the genetic determination of plasma ACE activity and its relation to blood pressure and dietary NaCl exposure in a model of experimental genetic hypertension, the SHRSPHD.
Methods and Results We conducted a further crossbreeding experiment between SHRSPHD and a congenic reference strain, WKYHD-1, that carries a 6-centimorgan (cM) long, SHRSP-homologous segment introgressed in chromosome 10, 26 cM remote from ACE. This allowed us to contrast effects on blood pressure and ACE activity conferred by the ACE locus with other more remote loci within the congenic chromosomal region. Genetic analysis in this F2 (WKYHD-1xSHRSPHD) cross revealed that plasma ACE activity was determined almost entirely by genetic effects of the ACE gene locus (lod score=43). However, neither plasma ACE nor the ACE locus showed any cosegregation with blood pressure before or after dietary NaCl exposure.
Conclusions These results demonstrate that a molecular variant of the ACE gene determines plasma ACE activity but exhibits no direct effect on blood pressure. Moreover, the findings also exclude the possibility that plasma ACE is secondarily affected by blood pressure or excess dietary NaCl exposure. Our results reconcile the previous discrepancy between findings in human and experimental hypertension.
Key Words: hypertension • genes • angiotensin • enzymes
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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An insertion/deletion polymorphism in intron 16 of the human ACE gene1 has been found to be in close linkage disequilibrium with an as yet unidentified mutation that accounts for 44% of the total variance of plasma angiotensin-converting enzyme (ACE) activity.2 Although controversy exists about a possible association of the DD genotype with certain cardiovascular disorders3 4 5 6 7 8 —the association of the D allele with higher ACE plasma levels has been advanced as a possible explanation3 —present evidence indicates that allelic variants of the ACE gene do not contribute to hypertension in humans,9 10 11 12 although occasional positive associations between the DD genotype and hypertension have been reported.13 14
Our previous crossbreeding studies15 16 in a rat model of spontaneous hypertension demonstrated linkage of the ACE gene, which is localized within a quantitative trait locus on chromosome 10 (BP/SP-1), with hypertension after excess dietary NaCl intake. BP/SP-1 showed significant linkage to high blood pressure under conditions of dietary NaCl exposure in a segregating F2-intercross population between the stroke-prone spontaneously hypertensive rat (SHRSPHD) and the normotensive Wistar-Kyoto (WKYHD-0) reference strain.15 16 Also, male but not female mice carrying a heterozygous disruption of the ACE gene have recently been found to have lower blood pressures than control mice, although serum ACE activities were significantly decreased in both sexes.17 Our determination of plasma ACE activity in the WKYHD-0 and SHRSPHD rat strains demonstrated a striking difference in plasma ACE activity, with twofold higher levels in the normotensive strain.18 Previous investigations had demonstrated similar tissue ACE activities among the two strains18 and no significant interstrain differences in the cDNA sequence or in vitro enzyme kinetics among SHRSPHD and WKYHD-0.19 Thus, despite the positive linkage data, it appeared difficult to envision a way in which the ACE gene could contribute to the pathogenesis of hypertension in SHRSPHD. Although ACE levels are, curiously, higher in normotensive rats, the clear difference between the strains may point either to a differential regulation of plasma ACE between the strains or to a secondary modulation as a consequence of increased blood pressure. Taken together, observations in the rat model are consistent with but not conclusive of the notion that allelic variants of the ACE gene may contribute causally to blood pressure differences between the SHRSPHD and WKYHD-0. To address whether plasma ACE levels are genetically determined and whether they contribute to blood pressure regulation or are modulated by blood pressure or NaCl diet, we conducted an additional cosegregation study.
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Methods |
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Animals and Genetic Crosses
Animals were obtained from our colonies of SHRSPHD, WKYHD-0, and WKYHD-1 rats at the University of Heidelberg, Germany.20 The experimental procedures for animal housing and breeding have been reported previously.20 The genetic and phenotypic characteristics of the WKYHD-0 and the WKYHD strains have been reported elsewhere, as has the F2 (WKYHDx SHRSPHD) population used in the present study.21
Blood Pressure Measurement
The protocol for the hemodynamic
characterization of the progenitor strains and the F2 rats
was identical. It included femoral artery cannulation and intermittent
on-line recordings as reported previously.20
Two consecutive femoral artery cannulations to measure blood pressure
were performed at baseline and after a period of 12 days of dietary
NaCl exposure (1% NaCl in the drinking water).20 After
completion of each recording session, blood was drawn from the
arterial catheter in conscious animals. Plasma ACE activity
levels were determined using a fluorometric method as described
previously.22
Genotype Determination
SSLPs markers of rat chromosome
1016 21 23
including the ACE marker were amplified by polymerase chain
reaction (PCR) from 50 ng of genomic DNA in a final reaction volume of
10 µL containing 100 nmol/L of each primer, 200 µmol/L dNTPs, 1.5
mmol/L MgCl2, 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH
9.0 at 25°C), 0.1% Triton X-100, and 0.25 U Taq DNA
polymerase. The forward primer was labeled with
[
-32P]ATP (specific activity 3000
Ci/mmol->1, DuPont/New
England Nuclear) by use of T4 polynucleotide kinase
(NEB). PCR reactions were processed on an MJ Research Thermal Cycler
(PTC 100, MJ Research) by use of the following protocol: initial
denaturation at 92°C for 3 minutes, followed by 30 cycles of
denaturation at 92°C for 15 seconds, annealing for 1 minute, and
extension at 72°C for 1 minute, followed by a final extension step at
72°C for 7 minutes. After the PCR reaction, the samples were
analyzed by polyacrylamide gel electrophoresis and
autoradiography as described
previously.16
Statistical and Linkage Analysis
Interstrain comparisons of
physiological
phenotypes were performed by two-way ANOVA, accounting for
influences of strain and sex. Statistical evaluation of the effects of
the ACE locus on phenotypes in the
F2-intercross was carried out by ANCOVA to account for
genotype, sex, and parental constellation of the reciprocal
crosses.16 For linkage analyses, means in each
group were adjusted for sex and reciprocal cross.16 Lod
scores were calculated with the LINKAGE programs as
reported previously.24 Correlation analysis was
performed using Pearson 
2 test. All
phenotype parameters are expressed as mean±SD.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Blood Pressure and Plasma ACE Activity in Parental Strains
Plasma ACE activity was twofold higher in WKYHD-0 compared with SHRSPHD, which contrasts with the blood pressure difference that is found between the strains (Table 1
). Basal and NaCl–loaded blood pressure showed a
sexual dimorphism with higher blood pressure in males than females
among SHRSPHD, whereas plasma ACE levels were not
different between sexes in either strain (Table 1).
Blood pressures increased significantly in response to excess dietary
NaCl in SHRSPHD, but plasma ACE levels were not
affected by NaCl. No differences between values at baseline and after
NaCl exposure were found either for blood pressure or for plasma ACE
activity in the normotensive strain.
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Genetic Analysis of Plasma ACE and Blood Pressure in an
F2 (WKYHD-1xSHRSPHD)
Cross
Genotypes were determined for 11 informative DNA
polymorphisms6 21 23 spanning a genetic
distance of 90
cM on chromosome 10. No significant genetic linkage between the
ACE locus and any of the blood pressure phenotypes
investigated was observed in the F2
(WKYHD-1xSHRSPHD) cross (Table 2).
In contrast, zygosity at the ACE locus
exhibited a strong effect on overall plasma ACE variance (Table
2). No significant differences between sexes or between
conditions at baseline and after NaCl exposure were found. The maximal
lod score of 43 for linkage to plasma ACE was detected at the
ACE gene locus, with flanking markers at 11 and 13 cM on
either side showing lod scores of 24 and 22, respectively. Plasma ACE
levels showed no correlation with blood pressure (see
Figure).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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ACE plays a key role in the catalysis of the renin-angiotensin and kallikrein-kinin systems, both of which are considered important regulators of cardiovascular homeostasis.25 Pharmacological compounds that are targeted to inhibit this enzyme (ACE inhibitors) have been found to reduce morbidity and mortality after myocardial infarction.26 27 28 Thus, it is important to identify the genetic mechanisms as well as the physiological parameters that are involved in the regulation of plasma ACE.
Using congenic experimentation, we recently demonstrated that the BP/SP-1 locus that contains ACE comprises at least two independent gene loci.21 One of them, BP/SP-1a, represents a 6 cM-long, SHRSP-homologous segment introgressed into chromosome 10 of the congenic line, WKYHD-1, 26 cM remote from ACE. This congenic segment has been shown to confer increased blood pressure to WKYHD-1.21 WKYHD-0 and WKYHD-1 are genetically identical at the ACE locus21 and accordingly show similar plasma ACE activity levels (data not shown). Nonetheless, we found complete absence of linkage between blood pressure and ACE genotype in an F2-population bred from WKYHD-1 and SHRSPHD.
This experiment thus provided us with an opportunity to study whether plasma ACE levels in the rat are genetically determined or whether they are secondarily affected by blood pressure. Plasma ACE was found to be tightly linked to the ACE locus in both male and female animals. The mode of inheritance was additive; linkage was also manifest after dietary NaCl exposure; and the ACE locus accounted for 89% of the overall variance of plasma ACE. In contrast, no association of plasma ACE and blood pressure was found, indicating a dissociation between genetic determinants for blood pressure and plasma ACE. Furthermore, our data also exclude the possibility that plasma ACE is secondarily and indirectly modified by blood pressure variance.
Our data demonstrate that genetic variation at the ACE locus determines differential plasma ACE activities among the WKYHD and SHRSPHD rat strains, much as it does in humans.1 In contrast, our high-resolution mapping and congenic experiments that allowed us to distinguish between the ACE gene and other genes within the previously demonstrated locus rule out a direct role of the ACE gene in the pathogenesis of hypertension in the SHRSPHD strain. This finding again corroborates the experience in human hypertension.9 10 11 12 To our knowledge, the present study represents the first demonstration that a quantitative trait locus confers concordant effects in humans and rats on a complex cardiovascular phenotype. On the basis of these results, we can reconcile the established discrepancies about the role of ACE in human and experimental hypertension.
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Acknowledgments |
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This work was supported in part by a Grant-in-Aid from the Massachusetts Affiliate of the American Heart Association (to Dr Lindpaintner), by the Deutsche Forschungsgemeinschaft (by grant no. Kr1152/1-1 to Dr Kreutz), and by the EURHYPGEN concerted action of the European Economic Community. Dr Kreutz is the recipient of a Howard Hughes Medical Institute research fellowship for physicians. Dr Lindpaintner is the recipient of NIH research career development award no. K04HL03039.
Received August 14, 1995; revision received September 5, 1995; accepted September 11, 1995.
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