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(Hypertension. 2000;35:1141.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Heritability of Angiotensin-Converting Enzyme and Angiotensinogen
A Comparison of US Blacks and Nigerians
From the Department of Preventive Medicine and Epidemiology (R.S.C., X.G., C.N.R., A.L.), Loyola University Stritch School of Medicine, Maywood, Ill; Department of Biological Anthropology (R.W.), Oxford University, Oxford, UK; University College Hospital (A.A.), University of Ibadan, Ibadan, Nigeria; and Department of Anesthesiology (S.M.D.), University of Illinois School of Medicine, Chicago, Ill.
Correspondence to Dr Richard S. Cooper, Department of Preventive Medicine and Epidemiology, Loyola University Stritch School of Medicine, 2160 S First Ave, Maywood, IL 60153. E-mail rcooper{at}luc.edu
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Abstract |
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Abstract—Angiotensinogen (AGT) and angiotensin I–converting enzyme (ACE) are heritable traits, but whether the environmental context influences heritability has not been examined. Known genetic factors explain only a portion of variation in AGT and ACE, and levels of both proteins are influenced by the environment. The African diaspora provides an opportunity to compare these traits in genetically related populations in contrasting environments. As part of a study of the genetics of hypertension, we examined families that included 1449 Nigerians and 1147 African Americans. Body mass index (weight [kg]/height [m]2) was 21 kg/m2 in Nigeria and 29 kg/m2 in the United States, which is consistent with a large environmental contrast. AGT was considerably higher among African Americans (1919 versus 1396, P<0.01), whereas ACE was higher in Nigerians (630 versus 517, P<0.01). A household effect was observed among the Nigerian families (spouse correlations 0.30 for AGT, 0.18 for ACE), and correlations among first-degree relatives were large (0.42 to 0.51 and 0.36 to 0.38 for AGT and ACE, respectively). Among African Americans, the familial aggregations of AGT and ACE were very limited, and the familial correlation for AGT was not different from zero. Heritability was 77% for AGT and 67% for ACE in Nigeria and 18% for AGT and ACE in the United States. The familial patterns of body mass index and blood pressure were similar among both family sets. In conclusion, less familial aggregation was observed for AGT and ACE in the United States than in Nigeria, most likely reflecting a greater random individual environmental effect on these traits. Variation in heritability of traits could influence the power of epidemiological studies to identify genetic effects.
Key Words: angiotensin-converting enzyme • angiotensinogen • genes • blacks • environment
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Introduction |
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The importance of modeling gene/environment interactions in the study of complex disorders is widely acknowledged.1 2 3 Although an extensive body of research exists in agriculture and plant research,4 5 very little is known about the differential expression of specific genetic traits in human populations. In fact, when the outcome of interest is chronic disease, formidable obstacles exist to such studies. The impact of the social environment is accumulated over many years, and under most circumstances, only the effect of a single exposure state can be observed for a given individual. Moreover, within contemporary societies, the range of lifestyle risk factors like being sedentary or high sodium intake tends to be narrow and exposure is essentially universal. The joint requirement of a constant genetic background and varying environmental exposures thus becomes extremely difficult to satisfy.
Although advances in molecular techniques provide the opportunity to identify functional variants in genes of interest, specific mutations have a small impact on most chronic conditions, and many pathways can lead to the same outcome. To gain some control over this complexity, physiological intermediates can be used. The renin-angiotensin system (RAS) plays a key role in blood pressure (BP) regulation, although its contribution to essential hypertension is still being defined.6 7 8 9 10 11 Molecular variants in the gene for angiotensinogen (AGT) modestly influence interindividual variation in blood level,6 7 whereas for angiotensin I–converting enzyme (ACE), 25% to 45% of the population variance is thought to be associated with the alu insertion/deletion motif.12 13 14 Thus, the RAS is a useful model system in studies of BP control and could provide the opportunity to examine gene/environment interactions. Because heritability represents the proportion of variance attributable to familial effects, its magnitude will vary inversely with the absolute variation contributed by random environmental effects at the individual level. Family sets can provide a first-order approximation of the extent to which the current observations about genetic effects on the RAS are influenced by the environment without the requirement of exhaustive information on the molecular mechanisms.
Migration studies are generally considered some of the most useful settings in which to search for gene/environment interactions in human populations.15 16 The direct examination of individuals before and after migration constitutes the most rigorous design, but rarely are sufficient numbers of people available for study under these circumstances. The historical migrations from traditional rural societies to industrialized cities that have occurred repeatedly in the modern world provide a useful alternative design. One of the largest of these diasporas occurred with the movement of West Africans to the Americas.17 18 19 These populations continue to share a common genetic heritage while being exposed to a gradient of lifestyles.20 As we previously demonstrated, this gradient results in a wide range of prevalence rates for common diseases, including hypertension, diabetes, obesity, and cardiovascular diseases.21 22 23 In the present report, we used the risk gradient along the African diaspora to examine changes in the familial patterns of circulating ACE and AGT in response to changes in the environment.
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Methods |
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Recruitment of Participants
The sampling frame for this study was provided by the International Collaborative Study on Hypertension in Blacks, as described elsewhere.21 24 Nuclear families were identified on the basis of a middle-aged proband, and available first-degree relatives were enrolled.25 26 Study protocols were reviewed and approved by the review boards of the participating institutions. The available family sets included 1993 persons from the United States and 2125 persons from Nigeria. Analyses were restricted to individuals with measurements of AGT (n=685 and 1053 for Nigeria and United States, respectively) or ACE (n=1449 and 1147 for Nigeria and United States, respectively).
The most common pedigree type encountered in Nigeria was father,
mother, and 
2 offspring, whereas in the United States, the most
common pedigree type was mother and 2 offspring. Of the 599 pedigrees
in Nigeria, 349 included both parents, compared with 82 of 543
pedigrees in the United States. Half-sibs were encountered frequently
in both populations, because of polygamy in Nigeria and remarriage in
the United States. Family members in both sites were not necessarily
residing in the same household, as among adult sibs, for example.
Genotyping at candidate loci made it possible to examine two thirds of
the pedigree relationships; a misspecification rate of 5% to 10% was
encountered in both populations.
Survey Methods
A screening examination was completed in a clinic setting by
trained research staff with a rigidly standardized
protocol.21 24 Height and weight were measured, and a
medical history was obtained. BP readings were taken with an automated
device (Omron), and the mean of the last 2 values was used in the
analyses. Body mass index (BMI) was calculated as weight
(kg)/height (m)2. Because the focus of this study
was on hypertension, probands were chosen because of their elevated BP.
Participants in Nigeria were more likely to have untreated BPs,
resulting in higher mean values in Nigeria than in the United States.
However, these values are not characteristic of the population as a
whole.21
AGT was measured through the generation of angiotensin I after incubation with excess human renin and is expressed as ng/mL.27 The interassay CV was 5.5%, and the intra-assay CV was 7% (n=25 blind duplicates). ACE was measured with a sandwich ELISA.28 The interassay CV was 5.6%, and the intra-assay was 6.2% (n=60).
Statistical Methods
Preliminary analyses were performed using
SAS.29 To assess the pairwise correlation between traits,
we performed the analysis on both raw and adjusted values. To
determine which covariates (among gender, age,
age2, and age3) should be
adjusted, generalized linear model analyses were used. To
assess the familial pattern of these traits, we estimated familial
correlations for pairs of relatives fitting the data to a polygenic
model with the use of REGC in SAGE software.30
Wald’s test was used to test for equality of the 3 correlations
(spouse, parent-offspring, and sib-sib) simultaneously
between the 2 samples. Because BP, BMI, and ACE tend to vary at the
extremes of age, we repeated all of the analyses excluding
children (age 
14 years) and the elderly (age >70 years) for both the
raw and the adjusted data. Additional analyses were conducted
on the Maywood, Ill, sample with individuals on antihypertensive
medications excluded. An overall estimate of heritability, designated
H2, was calculated as
(rpo+rsib)(1+rfm)/(1+rfm+2rfmrpo),
where po is parent-offspring, sib is sibling, r is correlation, and fm
is father-mother, as previously described by Rice et
al.31
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Results |
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The ages of the participants were comparable in the 2 population samples (Table 1). Women had higher levels of AGT in both groups, and the mean values were 30% higher in the United States than in Nigeria. ACE levels, on the other hand, were modestly higher among men and among Nigerians of either gender, compared with African Americans. The degree of adiposity, as reflected in the average BMI, was substantially lower in Nigeria, whereas BPs were somewhat higher. As noted, the selective recruitment of hypertensives, who were less likely to be treated at the screening examination in Nigeria, accounts for the difference in BP. Persons younger than 18 years had significantly higher ACE levels (data not shown).
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The results from the correlation analyses are presented
in Tables 2 and 3 for Nigeria and the United States,
respectively. In Nigeria, AGT was negatively correlated with ACE
(r
-0.1, P<0.01) but positively correlated with BMI,
systolic BP (SBP), and diastolic BP (DBP). ACE was
also negatively correlated with BMI and DBP in the raw data
(P<0.01) but not in the adjusted data, suggesting a
confounding effect of gender and age. A different pattern was observed
in the US sample. AGT was only correlated with BMI and DBP in the raw
data; no significant correlations were observed between AGT and any of
the other traits in the adjusted data. ACE had essentially no
relationship with BP or BMI.
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=0; and Number of Observations for
Nigeria Sample1
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Familial correlations were estimated for the sample as a whole and
among persons older than 14 years and younger than 70 years (Tables 4 and 5).
In Nigeria, substantial correlations were apparent for all traits, with
the exception of BP among spouses. Evidence for familial aggregation of
AGT and ACE is quite clear, with significantly higher correlations
among first-degree relatives (both between parent-offspring pairs and
among siblings). Parent-offspring and sib-sib correlations for AGT in
the adjusted data were among the highest (r=0.42 and 0.51,
respectively), although this must be considered in the context of a
significant spouse correlation for the same variable
(r=0.30). The exclusion of children (ie, persons 14 years
old) and old people (ie, older than 70 years) did not substantially
alter these relationships. Adjustment of the traits with covariates did
remove some of the confounding effects, as seen from the differences in
the correlation estimates. Spouse and sibling correlations decreased
after adjustment of traits with gender or age effect, or both, whereas
parent-offspring correlations were usually increased, except for AGT in
Nigerians, which implies a confounding age effect. However, the
familial aggregation pattern did not change.
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In the US sample, on the other hand, much lower correlations were observed (Table 5). A marginally significant household effect was observed only for BMI and SBP when the adjusted data were limited to ages 14 to 70, whereas no apparent household effect for AGT, ACE, or DBP was detected. Stronger evidence of familial clustering was observed in Nigeria than in Maywood, Ill, even after control for gender and age effect, except for BMI. Familial correlations in the Maywood, Ill, sample are significantly different from those of the Nigerian sample for AGT, ACE, and SBP (P<0.001). However, there was no significant difference among the 3 correlations in the 2 samples for BMI (P=0.373). The influence of medication use appeared to be modest.
Heritability, as previously defined, was used to summarize overall familiality (Table 6). For AGT, the estimates ranged from 76% to 78% in Nigeria and from 15% to 23% in the United States, and a similar pattern was observed for ACE. For BMI, on the other hand, higher values were obtained in the United States than in Nigeria (43% versus 30%). For BP, heritability was consistently higher in Nigeria than in the United States, depending on the sample definitions and adjustments (35% to 48% versus 5% to 21%).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The genetic underpinnings of hypertension have been difficult to define. Although genotyping methods are rapidly improving, little progress has been made in accounting for the joint effect of the environment. Because genetic effects vary across environments, in both relative and absolute terms, more refined measures of environmental influences would increase the precision of genetic studies. We attempted to model familiality as a summary measure of the effect of shared household environment and genetic factors. By using populations with strong genetic resemblance as a means of controlling variation in allele frequencies, we controlled the variation in the genetic background between these 2 groups. The results demonstrate that patterns of familiality for the traits that we studied vary substantially in different social settings. The most striking finding was the stronger familial pattern for AGT and ACE among Nigerians compared with African Americans. BP also tended to have a stronger familial component in Nigeria, after covariate adjustment, whereas BMI aggregated to a greater degree in the United States.
The degree of familiality that we obtained for AGT in Nigeria is extremely high, and it is implausible to attribute it entirely to genetic factors; on the other hand, the family aggregation for ACE, BMI, and BP in Nigeria were in the range of those previously reported.32 We have no ready explanation for the AGT findings. To the best of our knowledge, obesity and gender are the only important modifiers of AGT, and their effects were controlled in the model. The mean difference in AGT across groups was very large, and an interaction could exist such that the relationships within families vary with the mean level in the population. The nature of the environmental factors that account for the 60% higher AGT levels in the United States has not been adequately studied. As we have shown, the correspondence between BMI and AGT at the population level is strong,33 and this relationship is thought to reflect body fat stores. However, obesity is a complex trait, and BMI could be functioning as an indicator variable for differences in eating patterns, sodium intake, and physical activity. It is possible, therefore, that BMI does not provide a sufficiently precise proxy for the factors that influence AGT. If these unmeasured environmental covariates aggregated within households in Nigeria, the apparent high degree of heritability could be explained.
Opposite to the finding in Nigeria, the familiality observed for AGT and ACE in the United States was surprisingly low. As an explanation of the comparative differences, the assumption must be made that random environmental effects at the individual level were greater in the United States. Although, as noted earlier, a class of effects that could be causal has yet to be described, overall differences in lifestyle can be easily identified. For example, in Nigerian households, eating patterns are more consistent, given the limited opportunities to find meals outside of the home, and extended families share the same living space for a greater proportion of the life span. Average levels of physical activity are much higher in Nigeria, and sodium intake is lower.21 On the basis of the estimates we obtained, however, the factors that lead to aggregation of BMI at the family level are if anything stronger in the United States. Finally, it is of interest that the contrast in heritability for BP itself was not as extreme as it was for the other traits. It is potentially possible that these 2 pathways, the RAS, reflecting sodium handling, and BMI, reflecting physical activity and obesity, aggregate in different patterns between these groups and contribute in different ways to heritability of BP.
Little comparative family data for these traits have been published. In a French study of 87 families, adjusted familial correlations for ACE were 0.38, 0.17, 0.32, and 0.30 for spouses, father-offspring, mother-offspring, and siblings, respectively.32 AGT is influenced by body composition,32 33 34 although specific environmental determinants for ACE are not well specified.34 35 Lung disease and some parasites can raise ACE; onchocerciasis, which is associated with elevated ACE, is endemic in Nigeria and might have contributed to the higher mean levels.36
Using larger family sets, Rice et al37 examined
heterogeneity of the familial relationships for BP in
the Quebec Family Study and the Tecumseh Community Health Study. With
the Tau model, higher spouse correlations were detected for SBP in
Quebec, with similar familiality (40%), whereas for DBP,
familiality was substantially higher in Quebec (60%) than in
Tecumseh (25%), leading to the interpretation of a larger effect of
household environment in Quebec.37 Control for
cohabitation eliminated most of the apparent excess familiality in the
Quebec sample. This general pattern of variation in familiality
parallels the contrasts we observed between Nigeria and Maywood, Ill.
However, it must be acknowledged that the large sample size available
to Rice et al made it possible to restrict the analyses to
individuals currently living together, an option not available in the
present study, and this might have yielded greater precision.
A number of difficulties arise in the interpretation of these data. As we described, family structures and living arrangement vary across these cultures, and systematic variation that we did not recognize could have biased our results. The age range of individuals enrolled in the study was quite broad, and sibships included both children and adults. Clearly, the shared environment will be different for children living in the same household and for adults who have lived apart for many years. Characterization of the relevant exposures that confer familiality would obviously be necessary to adjust for these effects; however, such measures do not yet exist.
In summary, we compared the familial patterns of components of the RAS in 2 populations of common ancestry in different social environments. Large differences in the mean levels of the traits, their associated familial aggregation, and the within-person physiological relationships were identified. The apparent interaction between familiality and AGT level was particularly striking. Some factors associated with the obesity syndrome may be the cause of this phenomenon; if this conjecture is correct, the identification of these factors might yield new insights into how lifestyle patterns influence the risk of hypertension. In addition, a better understanding of the range of variation in the familiality of BP and associated traits could lend greater precision to studies that attempt to isolate genetic effects.
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Acknowledgments |
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This work was supported by NHLBI grant HL-47910. Some of the results were obtained with SAGE, which is supported by grant P41-RR-03655 from the National Center for Research Resource. We want to express our appreciation to the staff of the Igborra Hospital for their help in the enrollment of the Nigerian participants.
Received August 13, 1999; first decision September 22, 1999; accepted December 13, 1999.
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