(Hypertension. 1996;27:62-66.)
© 1996 American Heart Association, Inc.
Articles |
Racial Difference in the Relationship of an Angiotensin I–Converting Enzyme Gene Polymorphism to Serum Angiotensin I– Converting Enzyme Activity
From the Department of Medicine, Indiana University School of Medicine, and the VA Hospital, Indianapolis.
Correspondence to J. Howard Pratt, MD, Department of Medicine, Indiana University School of Medicine, 541 Clinical Dr, Indianapolis, IN 46202. E-mail howardp@medicine.dmed.iupui.edu.
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Abstract |
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Abstract An insertion (I)/deletion (D) polymorphism of the angiotensin I–converting enzyme (ACE) gene that has been associated with certain cardiovascular disorders accounts for nearly half the variation in serum ACE level in white subjects. Whether a similar association of serum ACE with the I/D polymorphism occurs in other racial groups is not known. We studied the I/D polymorphism of ACE in relation to serum ACE activity in 141 white and 62 black healthy, unrelated children and adolescents (mean age, 14.7 years). The mean level of ACE activity in whites homozygous for the D allele was higher than in heterozygotes (P=.002) and in homozygotes for the I allele (P=.0001), consistent with an earlier study. In blacks, on the other hand, no significant difference in serum ACE activity between genotypes was observed. An additional finding was a significantly positive relationship between serum ACE activity and diastolic pressure (P=.009). In children and adolescents, serum ACE activity is related to the ACE gene I/D polymorphism in whites but not in blacks. The results indicate a potentially important ethnic variation in genetic regulation of serum ACE activity and the relationship of the I/D polymorphism to cardiovascular disease.
Key Words: angiotensin-converting enzyme • genes • blood pressure • blacks
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The functions of the dicarboxypeptidase ACE include the metabolism of bradykinin and the conversion of angiotensin I to angiotensin II.1 Angiotensin II is an octapeptide that has vasoactive and sodium-retaining activities along with a capacity to stimulate proliferation of vasculature.2 The level of serum ACE remains relatively constant over time in a given individual,3 whereas between individuals serum ACE varies approximately fivefold.3 4 A strong intrafamilial resemblance of serum ACE together with segregation studies suggest that a major gene regulates the circulating level.5 An I/D polymorphism of the ACE gene consisting of 287 bp within intron 166 was found to account for nearly half the variation in the serum ACE level in unrelated, healthy individuals.7 A more recent combined study of segregation and linkage indicated that the I/D polymorphism, although not directly responsible for the variation in serum ACE, was in linkage disequilibrium with the regulatory allele.8
The ACE gene I/D polymorphism may have important clinical relevance. A number of associations of the ACE gene I/D polymorphism with cardiovascular disease have now been recognized9 10 11 12 13 14 15 16 17 18 that may be related to the higher level of ACE that accompanies the presence of the D allele. On the other hand, the association of the I/D polymorphism with hypertension has been mostly inconclusive.19 20 21 22
The relationship of the ACE gene polymorphism and the level of serum ACE was described in a study that included only white subjects. Because of the migrations and separations of populations that have occurred over time, various degrees of genetic diversity have emerged between different racial groups.23 Thus, genetic association studies demonstrating relationships in one racial group require confirmation in other racial groups. In addition, there are well-established racial differences in the renin-angiotensin system, such as the lower PRA that typically occurs in blacks.24 25 26 In the present study we addressed whether the association of the ACE polymorphism with serum ACE activity observed in whites also occurs in blacks. If there are racial differences in the transcriptional regulation of ACE, then the previously reported associations of the ACE D allele may have less relevance for blacks. The study was performed in a cohort of children and adolescents that have been described previously.27
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Subjects
Subjects were recruited from an ongoing longitudinal BP study in children and adolescents from Indianapolis, Ind.27 Subjects in the original longitudinal study were recruited from 20 schools in Indianapolis to achieve a representation from diverse socioeconomic backgrounds. The study was approved by the Institutional Review Board of Indiana University–Purdue University of Indianapolis. Informed consent was obtained from each child as well as from his or her parents or legal guardian. Children with a history of hypertension, renal disease, cardiac disease, or diabetes mellitus as well as those taking medication that could affect BP or the renin-angiotensin system were excluded from the study. Subjects volunteered for the present study by providing a blood sample for isolation of DNA, measurements of plasma renin activity and aldosterone, and measurement of serum ACE activity. In the original group of subjects, 23 had at least one sibling also participating in the study. For preservation of the statistical independence among subjects, one sibling from each family was randomly selected for the statistical analyses. Hence, results are reported for 203 subjects.
Measurements
Weight and height were measured at the time
blood samples were
drawn. This took place either at the subject's school or at Indiana
University's General Clinical Research Center. Dietary conditions and
posture were not controlled. Because these subjects were participants
of an ongoing longitudinal study of BP, the BP values that had been
determined every 6 months during the previous 5 years were used in the
analyses. BP was measured in the right arm with a
random-zero sphygmomanometer (Hawksley and Sons) while the subject
was seated. The first and fifth Korotkoff sounds were used to designate
systolic and diastolic BPs, respectively. Three BP
readings were obtained, and the average of the last two readings was
used as the final BP measurement.
Identification of the I/D Polymorphism
Whole blood was
collected in EDTA-containing Vacutainer tubes.
DNA was extracted from the white cells according to a standard
procedure.28 The genomic region encompassing the 287-bp I
or D fragment was amplified by the polymerase chain reaction with the
use of oligonucleotide primers and reaction conditions
that have been described previously.7 The specific
alleles were identified after the amplified products were
subjected to agarose gel electrophoresis.
Assay Procedures
Plasma aldosterone concentration was
measured by
radioimmunoassay with antiserum from Diagnostic
Products Corp. PRA was measured with a Clinical Assays GammaCoat
radioimmunoassay kit (Baxter Healthcare). Serum ACE activity was
measured with a method described by Lieberman.29 One unit
of ACE activity equaled the nanomoles of hippuric acid formed per
minute at 37°C per milliliter of serum. To assess the reproducibility
of measurements of serum ACE activity, we used data from 23 individuals
whose serum ACE activity was measured twice within a 6-month period.
The Pearson correlation coefficient was .8, the coefficient of
variation was 7%, and the intraclass correlation was .8. Thus, the
levels of serum ACE activity were highly stable within an
individual.
Statistical Methods
The characteristics of white and black
subjects at the time
blood samples were drawn were compared with the use of a t
test. For determination of whether the serum ACE activity was related
to race and genotype, a two-way ANOVA was used. The main
effect terms race (1 df) and genotype (2
df) and the interaction term (2 df) between race
and genotype were included in the model. The significant
interaction term indicated that the relationship between serum ACE
activity and genotype was different in whites and blacks.
Because the overall interaction was significant, Fisher's
least-squares significant difference for multiple comparisons
procedure was used to find where the differences occurred. Longitudinal
BP values were used for examination of the relationship between BP and
race, genotype, and serum ACE activity with the use of the
methods introduced by Liang and Zeger.30 BP values were
adjusted for body size by including BMI as a covariate in the
model.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Subject Characteristics
Of the 203 subjects who participated in the study, the proportions of males (48% of whites and 54% of blacks) were not significantly different between the racial groups. Subject characteristics at the time blood samples were drawn are shown in Table 1
. The
age range for white subjects was 7.9 to 18.6 years and for black
subjects was 9.5 to 18.9 years. Although the average age of the two
groups was not significantly different, the black children were heavier
(P=.0006) and had a higher BMI (P=.0001) than
the
white children, consistent with previous studies in
children.31 The means of longitudinal systolic BP
were not significantly different in whites and blacks, whereas the
means of longitudinal diastolic BP were higher in the black
children (P=.002). Black children had on average 16% lower
PRA than white children, a difference that did not reach statistical
significance (P=.09). On the other hand, the plasma
aldosterone level was significantly lower in black children
(35% lower, with P<.001), as has been reported
previously.32 33 PRA and plasma aldosterone
were significantly related (r=.39, P<.0001),
whereas neither of these variables was related to serum ACE
activity (for PRA, r=-.03, P=.65; for
plasma aldosterone, r=.05,
P=.50).
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Frequencies of the D and I Alleles
Frequencies of the D
alleles were 0.54 and 0.64 and of the I
alleles were 0.46 and 0.36 in whites and blacks, respectively.
Allele frequencies were not significantly different between racial
groups (
2=3.14, 1 df,
P=.08), and distributions of genotypes were also
similar in whites and blacks (2=4.44, 2
df, P=.12). These results are similar to those
reported previously for whites and blacks.34
Genotype distributions in whites and blacks were
consistent with the populations being in Hardy-Weinberg
equilibrium.
Relationship of the ACE Genotype to Serum ACE
Activity
For determination of the relationship between serum ACE
activity,
genotype, and race, a two-way ANOVA was used. The data are
shown in the Figure. An overall significant interaction
between race and genotype (P=.024) indicated that
the relationships between genotype and serum ACE activity were
not the same for whites and blacks (after adjustment of ACE activity
for age and sex, the interaction was significant at P=.014).
For whites, the mean serum ACE activity in the DD group was
significantly higher than in the heterozygous group (P=.002,
Table 2) and significantly higher than in the II group
(P<.0001); ACE activity was also significantly different
between ID and II groups (P=.0009). For blacks, the mean ACE
activity did not change with the genotype; that is, for blacks
the mean ACE activity for the DD group was not significantly different
from that of the ID group (P=.26) or II group
(P=.17), nor was there a significant difference between ID
and II groups (P=.37). Since there were few blacks
homozygous for the I allele, we reanalyzed the data
after removing all II white and black subjects. The interaction of race
with serum ACE activity and genotype remained significant
(P=.024), and the difference between DD and ID groups
continued to be significant for whites (P<.0001) but not
for blacks (P=.44). We also examined the effect of extreme
observations on the results of the statistical analysis. When
the highest ACE activity value for the II or DD group was deleted or if
both of these outliers were deleted, the interactions remained highly
significant (eg, when both were deleted, the interaction was
significant, with P=.001). Thus, the overall conclusions
remained unchanged.
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There was a significantly negative relationship
between serum ACE
activity and age (r=-.17, P=.015), an
observation that has been made by others.29 35
Age-adjusted means for serum ACE activity in relation to
genotype are presented in Table 2
; differences between
genotype groups after the adjustment were the same as for
unadjusted values. After adjustment for age, the interaction of race
with serum ACE activity and genotype remained significant
(P=.014). The mean level of serum ACE activity was 26%
higher in males than in females (P<.0001), a result similar
to a previously reported observation.29
Relationship of ACE Genotype and Serum ACE Activity
to BP
Since body size was highly related to both systolic and
diastolic BPs (P<.0001), we used regression
techniques to adjust the longitudinal BP values for BMI as well as for
race and sex. A series of models were fitted to analyze the
longitudinal BP, including an examination of the change in BP over
time, because we showed previously for this same cohort that BP
increased faster in the blacks than whites.27 However, we
found no significant association between the longitudinal BP and
genotype (BP unadjusted for body size also showed no
relationship to genotype). BP also showed no significant
relationship with either plasma aldosterone
(r=.05 for systolic, r=.07 for
diastolic) or PRA (r=.04 for systolic,
r=.002 for diastolic). On the other hand, serum
ACE activity showed a significantly positive association with the mean
longitudinal diastolic BP (P=.009) and a
marginal association with the mean longitudinal systolic BP
(P=.078) after adjustment of BP for race, sex, and BMI.
Diastolic BP unadjusted for body size was also related to
serum ACE activity (P=.035), whereas systolic BP was
not (P=.28). The regression coefficients for serum ACE
activity with systolic and diastolic BPs were
0.09±0.04 (SE) and 0.11±0.04 U/mL, respectively. Thus, after
accounting for BMI, race, and sex an increase in serum ACE activity of
10 U/mL would be predicted to increase systolic BP by 0.9
mm Hg and diastolic BP by 1.1 mm Hg.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Results of the present study of white children confirm the previously described association of the ACE gene I/D polymorphism with serum ACE observed in white adults7 : The level of ACE activity was significantly higher in the white children with D alleles than with I alleles, whereas the level of ACE activity was intermediate in those who were heterozygous. On the other hand, in the black children, no association of the I/D polymorphism with serum ACE activity was found. There was thus a distinctly different association of the ACE gene polymorphism with the regulation of serum ACE activity in white and black children.
Although in the present study there were fewer black subjects,
especially in the II group, for the following reasons we feel that the
absence of a significant association in blacks was not secondary to the
smaller number of subjects. First, there was a significant interaction
of race with the relationship of genotype to serum ACE activity
(P=.02). Second, a power analysis indicated
sufficient statistical power between the ID and DD groups.
Specifically, going from ID (n=31 blacks) to DD (n=25 blacks),
with the
use of a previously reported standard deviation of 9.3
U/mL12 and application of a significance level of
=.05
with a two-sided Student's t test, there were powers of
80% and 95% to detect differences of 7 and 9 U/mL of ACE activity,
respectively. We did observe in the blacks a slight but nonsignificant
trend toward a higher level of ACE activity when going from the II to
DD genotype. Conceivably, a significant difference between
genotype groups, albeit much smaller than in whites, might be
observed if a sufficiently large number of blacks were studied. This
would occur, at least to some extent, because of the admixture of genes
of white origin in American blacks.36 37
A recent study using a combined segregation and linkage analysis8 showed that the ACE I/D polymorphism was a neutral marker in linkage disequilibrium with an allele that regulated serum ACE activity. Our results support this conclusion because blacks in the present study were carriers of both the I and D alleles, yet these alleles were not associated with serum ACE activity. The two alleles controlling the level of serum ACE activity in white subjects were designated "S" and "s,"8 where S results in higher serum ACE activity and s in lower ACE activity. The postulated S allele was shown to be associated mostly with the D allele,12 whereas the s allele was associated primarily with the I allele.8 The levels of ACE activity in the blacks of our study were distributed over a range similar to that observed in whites, suggesting that S or an allele like S that results in a higher level of ACE activity may also occur in blacks. However, whether a major gene effect can explain the wide range of ACE activity in blacks will have to await a study of segregation analysis using additional family members.
ACE occurs in two major forms: a circulating or "soluble" serum enzyme and an ectoenzyme bound to cell membranes.1 Serum ACE appears to be derived from cleavage of membrane-bound endothelial ACE.38 39 Membrane-bound ACE in circulating lymphocytes and the serum ACE were found to be similarly associated with the I/D polymorphism,40 suggesting that the putative S allele regulates the ACE gene at the transcriptional or translational level as opposed to one affecting the cleavage of membrane-bound enzyme.
A number of associations of the ACE polymorphism with cardiovascular disease have been described recently. These include associations with myocardial infarction,9 10 11 12 13 albeit an association that has been inconsistent,14 15 16 and left ventricular hypertrophy.17 Among hypertensive individuals, the D allele was found to be less frequent in groups of individuals who were older,18 suggesting that the D allele conveys an increase in risk of early cardiovascular death. However, another study found that centenarians have an increased frequency of the D allele.41 All of these clinical associations were made in studies of white subjects. Since relationships with the ACE polymorphism may be conveyed by the level of ACE activity, our current findings suggest that these reported associations may be limited only to certain racial groups.
ACE level may be increased in patients with sarcoidosis,29 and it has been suggested that ACE level is optimally interpreted in the presence of information about the individual's ACE genotype.7 Our findings again indicate caution in applying this recommendation to black individuals, an ethnic group in which sarcoidosis is comparatively common.42
Since ACE activity is an integral component of the renin-angiotensin system, ACE has been considered a candidate gene for hypertension. Evidence from transfection studies suggests that ACE expression may be related to actions conveyed by angiotensin II2 ; thus, ACE activity could be rate limiting for angiotensin II generation. In the stroke-prone spontaneously hypertensive rat, a region on chromosome 10 inclusive of ACE showed linkage to hypertension.43 44 However, in a human study, there was no linkage to hypertension of a conserved region on chromosome 17 encompassing ACE.45 To date, association studies of the ACE I/D polymorphism with either hypertension or a predisposition to hypertension have provided inconsistent findings.19 20 21 22 In the present study the longitudinal BP estimated from repeated measurements over 5 years was used in the analyses. No association of the I/D polymorphism with BP was observed. There was, however, an interesting significantly positive association of serum ACE activity with systolic BP and a marginally significant association with diastolic BP. We found no evidence that the level of serum ACE activity was reflective of a variable more directly related to BP such as body size. ACE activity was negatively related to age, and thus adjustments for age (or body size, since the two are highly related) actually strengthened the significance of the relation of serum ACE activity to BP. A similarly significant relationship of serum ACE with BP in children was observed by Tiret et al,8 and Alhenc-Gelas et al4 found a significant relationship of serum ACE with systolic BP in normotensive adults. Furthermore, hypertensive compared with normotensive subjects had higher serum ACE levels in one study46 although not in another.3
In summary, in contrast to findings in whites, we found no significant association of an ACE I/D polymorphism with serum ACE activity in black children and adolescents. The findings are consistent with a distinct racial difference in how serum ACE activity is regulated in relation to the ACE gene polymorphism. Earlier findings that associated the ACE I/D polymorphism to certain clinical conditions in white subjects may not be relevant to individuals with different racial backgrounds.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the National Institutes of Health (R01-HL-37795 and MO1-RR-00750) and the Veterans Administration. We are grateful for the excellent technical assistance of Mary Anne Wagner, BA, and Chunlu Guo, MD.
Received April 27, 1995; first decision June 30, 1995; accepted September 6, 1995.
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 Y.-Y. Hsieh, C.-C. Chang, F.-J. Tsai, C.-M. Hsu, C.-C. Lin, and C.-H. Tsai Angiotensin I-converting enzyme ACE 2350*G and ACE-240*T-related genotypes and alleles are associated with higher susceptibility to endometriosis Mol. Hum. Reprod., January 1, 2005; 11(1): 11 - 14. [Abstract] [Full Text] [PDF]
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 V. Wiwanitkit Angiotensin-converting Enzyme Gene Polymorphism: I and D Alleles From Some Different Countries Clinical and Applied Thrombosis/Hemostasis, April 1, 2004; 10(2): 179 - 182. [Abstract] [PDF]
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 S. B. Harrap, C. Tzourio, F. Cambien, O. Poirier, S. Raoux, J. Chalmers, N. Chapman, S. Colman, S. Leguennec, S. MacMahon, et al. The ACE Gene I/D Polymorphism Is Not Associated With the Blood Pressure and Cardiovascular Benefits of ACE Inhibition Hypertension, September 1, 2003; 42(3): 297 - 303. [Abstract] [Full Text] [PDF]
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 P. L. Kimmel, L. Barisoni, and J. B. Kopp Pathogenesis and Treatment of HIV-Associated Renal Diseases: Lessons from Clinical and Animal Studies, Molecular Pathologic Correlations, and Genetic Investigations Ann Intern Med, August 5, 2003; 139(3): 214 - 226. [Abstract] [Full Text] [PDF]
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 A. Bouzamondo, J.-S. Hulot, P. Sanchez, and P. Lechat Beta-blocker benefit according to severity of heart failure Eur J Heart Fail, June 1, 2003; 5(3): 281 - 289. [Abstract] [Full Text] [PDF]
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J. H. Pratt, W. T. Ambrosius, R. Agarwal, G. J. Eckert, and S. Newman Racial Difference in the Activity of the Amiloride-Sensitive Epithelial Sodium Channel Hypertension, December 1, 2002; 40(6): 903 - 908. [Abstract] [Full Text] [PDF]
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W. X. Liao and A. C. Roy Lack of association between polymorphisms in the testis-specific angiotensin converting enzyme gene and male infertility in an Asian population Mol. Hum. Reprod., March 1, 2002; 8(3): 299 - 303. [Abstract] [Full Text] [PDF]
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 D. S. McGRATH, P. J. FOLEY, M. PETREK, L. IZAKOVICOVA-HOLLA, V. DOLEK, S. VEERARAGHAVAN, P. A. LYMPANY, P. PANTELIDIS, A. VASKU, A. U. WELLS, et al. ACE Gene I/D Polymorphism and Sarcoidosis Pulmonary Disease Severity Am. J. Respir. Crit. Care Med., July 15, 2001; 164(2): 197 - 201. [Abstract] [Full Text] [PDF]
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 The Beta-Blocker Evaluation of Survival Trial Inve A Trial of the Beta-Blocker Bucindolol in Patients with Advanced Chronic Heart Failure N. Engl. J. Med., May 31, 2001; 344(22): 1659 - 1667. [Abstract] [Full Text] [PDF]
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J. V. Gainer, C. M. Stein, T. Neal, D. E. Vaughan, and N. J. Brown Interactive Effect of Ethnicity and ACE Insertion/Deletion Polymorphism on Vascular Reactivity Hypertension, January 1, 2001; 37(1): 46 - 51. [Abstract] [Full Text] [PDF]
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C. J. Young and R. S. Gaston Renal Transplantation in Black Americans N. Engl. J. Med., November 23, 2000; 343(21): 1545 - 1552. [Full Text] [PDF]
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 M.-C. Hsieh, S.-R. Lin, T.-J. Hsieh, C.-H. Hsu, H.-C. Chen, S.-J. Shin, and J.-H. Tsai Increased frequency of angiotensin-converting enzyme DD genotype in patients with type 2 diabetes in Taiwan Nephrol. Dial. Transplant., July 1, 2000; 15(7): 1008 - 1013. [Abstract] [Full Text] [PDF]
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 B. Agerholm-Larsen, B. G. Nordestgaard, and A. Tybjarg-Hansen ACE Gene Polymorphism in Cardiovascular Disease : Meta-Analyses of Small and Large Studies in Whites Arterioscler. Thromb. Vasc. Biol., February 1, 2000; 20(2): 484 - 492. [Abstract] [Full Text] [PDF]
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 S JEFFERY, A K S. MALIK, A CROSBY, M BLAND, J B EASTWOOD, J AMOAH-DANQUAH, J W ACHEAMPONG, and J PLANGE-RHULE A dominant relationship between the ACE D allele and serum ACE levels in a Ghanaian population J. Med. Genet., November 1, 1999; 36(11): 869 - 870. [Full Text]
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M. J. MALIARIK, B. A. RYBICKI, E. MALVITZ, R. G. SHEFFER, M. MAJOR, J. POPOVICH Jr., and M. C. IANNUZZI Angiotensin-converting Enzyme Gene Polymorphism and Risk of Sarcoidosis Am. J. Respir. Crit. Care Med., November 1, 1998; 158(5): 1566 - 1570. [Abstract] [Full Text] [PDF]
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 C. J. O'Donnell, K. Lindpaintner, M. G. Larson, V. S. Rao, J. M. Ordovas, E. J. Schaefer, R. H. Myers, and D. Levy Evidence for Association and Genetic Linkage of the Angiotensin-Converting Enzyme Locus With Hypertension and Blood Pressure in Men but Not Women in the Framingham Heart Study Circulation, May 19, 1998; 97(18): 1766 - 1772. [Abstract] [Full Text] [PDF]
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