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(Hypertension. 1995;26:919-924.)
© 1995 American Heart Association, Inc.
Articles |
Heritability of Conventional and Ambulatory Blood Pressures
A Study in Twins
From the Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research (R.F., J.B., J.S., L.T.), and the Department of Human Genetics (C.D., M.T., R.V.), Faculty of Medicine, University of Leuven (Belgium).
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Abstract |
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Abstract Conventional and 24-hour ambulatory blood pressures were measured in 26 pairs of monozygotic twins and 27 pairs of dizygotic twins, all male, ages 18 to 38 years, to determine the heritability of blood pressure measured under various conditions. Conventional pressure was the average of three well-standardized measurements in the supine position, and ambulatory pressure was recorded during the subjects' normal activities by use of the SpaceLabs 90202 device. Heritability was assessed by classic methods and by model fitting and path analysis. In the latter approach, the percent genetic variance was 70% for mean 24-hour systolic pressure and 73% for diastolic pressure, which was similar to the results for the conventional pressures (64% and 73%, respectively). During the night, these estimates were 72% and 51% for systolic and diastolic pressures, respectively, and also the average pressures of the total awake daytime period were under partial genetic control (63% and 55%, respectively). The remaining variances could be attributed primarily to unique environmental influences. However, shared and nonshared environmental factors were predominant for the pressures during a fixed 6-hour afternoon period. We conclude that the heritability of blood pressure is relatively high in young adult healthy men, for standardized conventional pressure and the average 24-hour pressure. Genetic variance is somewhat higher for the asleep pressure than for the awake systolic pressure.
Key Words: blood pressure, ambulatory • genetics • twins
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Introduction |
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There can be no doubt that blood pressure in humans is the result of a complex interplay between genetic and environmental factors.1 Significant genetic variance has been shown repeatedly in studies in families2 3 4 5 and in monozygotic and dizygotic twins.4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 The variation in blood pressure that can be attributed to genes has been estimated at 30% to 60%.1 Most authors have reported on conventional blood pressure, measured in the population, in the hospital or under laboratory conditions. The disadvantages of these measurements are well-recognized: Their number is limited, they represent only a small period of time during the daytime, and they may be influenced by the unusual conditions and the presence of the investigator, referred to as the white coat effect.20 21 Heritability estimates may be affected by these factors. The availability of ambulatory blood pressure recorders, by contrast, allows us to measure blood pressure repeatedly during the day and the night, outside of the hospital, in the subjects' natural environment.21 Application of this technique in twins permits us to assess the proportion of the variance of blood pressure that can be attributed to inheritance and the proportion that can be attributed to environmental factors at various times throughout the day, during the subjects' usual activities. It can reasonably be assumed that environmental factors are more prevalent during the day than during the night. However, this was not observed by Degaute et al,18 who reported on ambulatory blood pressure in twins; their findings could be related to the fact that the twins were admitted to the hospital and spent the night in a sleep laboratory where polygraphic sleep recordings were performed. In the present study, blood pressure was measured in young male monozygotic and dizygotic twins, both under well-standardized laboratory conditions and during their normal activities for a 24-hour period. In addition to the classic analysis of twin data,22 the model-fitting and path analysis approach has been applied in which the contributions of genetic, shared, and nonshared environmental factors and of phenotypic interaction were considered.23
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Methods |
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Subjects
One hundred and six 18- to 38-year-old healthy men (26 pairs of monozygotic and 27 pairs of dizygotic twins) were studied. The study was approved by the Ethics Committee of the Faculty of Medicine, and all subjects provided informed consent. Twins were drawn from the East Flanders Prospective Twin Study, in which zygosity was determined at birth, including determination of DNA polymorphism24 and by checking of municipal and parish registers in several Flemish towns and lists of students in the schools of the Leuven area and the University of Leuven. In the latter twin pairs, the phenotype of the subjects was compatible with the zygosity reported by the twins, which was based on their own or their parents' subjective assessment,25 what was communicated to the parents at birth, or on results from a former serological examination. In case of uncertainty, zygosity was tested. These twins underwent a serological examination (ABO; Rhesus, subgroups; MNS; Kidd; Kell; and Duffy) and determination of the HLA system (A, B, C, and DR loci) and the chromosomal polymorphism.
Protocol
Twins were tested in pairs in the morning in an
air-conditioned laboratory. They were separated to fill in a
questionnaire on general health, living conditions, and lifestyle,
including marital status; whether they lived together, partially apart,
or totally apart; current smoking habits and alcohol consumption;
weekly hours of sports activity; and personal estimates of habitual
physical activity and psychological stress, both on a scale from 0 to
10. Investigations included measurements of height and weight and a
physical examination. After 10 minutes of supine rest, blood pressure
was measured in triplicate by sphygmomanometry and auscultation
(Korotkoff phases I and V), always by the same investigator; the
reported conventional pressure is the average of the three
measurements. Heart rate was counted during 30 seconds and expressed as
beats per minute (bpm).
The ambulatory blood pressure monitor (SpaceLabs 90202; SpaceLabs, Inc) was then applied, and the subjects resumed their normal activities. The recorders were programmed to obtain measurements every 20 minutes from 8 AM to 10 PM and every 30 minutes between 10 PM and 8 AM. The subjects noted the time they went to bed and the time they woke up to determine the "awake" and "asleep" periods. In addition to the exclusion of readings that were not successfully completed by the monitor, the recordings were edited before further analysis by the removal of clear outliers on visual inspection of the individual curves (that is, three systolic blood pressure recordings above 200 mm Hg and five diastolic pressures above 150 mm Hg). The recordings were then analyzed as follows: (1) The blood pressures and heart rates from the periods when the subjects were in bed (asleep period) and out of bed (awake period) were averaged. The 24-hour means were calculated as the time-weighted averages of these two periods. In addition, the mean pressures of a fixed 6-hour period during the day (ie, from 2 PM to 8 PM) were analyzed. (2) The mean blood pressures of the consecutive 6-hour periods of highest (crest) and lowest (trough) pressures, which are independent of fixed time periods, were derived by use of the cumulative sum (cusum) technique.26
The awake and asleep periods lasted (mean±SD) 15.4±1.5 and 8.6±1.5 hours, respectively, and did not differ between the monozygotic and dizygotic twins. Two subjects were excluded from the analysis of ambulatory blood pressure during the awake period and four for the asleep period because only five or less valid measurements were available. In the others, 40±6 blood pressures were recorded when subjects were out of bed and 17±4 blood pressures when in bed; these numbers were related significantly to the duration of the periods (P<.001). Subjects were excluded from cusum analysis when there were no valid measurements in any 2-hour period, which was the case in eight subjects during the day and nine during the night.
Statistical Analysis
The analysis of twin data was performed by ANOVA and by
the model-fitting and path analysis approach. Average data
of the individual subjects in each twin group are reported as mean±SD
or as mean and total variance. Possible associations of the mean and
the total variance with the twin type were tested as described by
Christian.22 In a first approach and to allow comparison
with several previous studies, the intraclass correlation coefficients
within each twin type (rMZ and rDZ) were then
calculated from the among- and within-pair mean squares as
(among-pair-within-pair mean
square)/(among-pair+within-pair mean square). Several
heritability estimates can be derived from the mean squares and
intraclass coefficients.27 The estimate proposed by Newman
[h2=(rMZ-rDZ)/(1-rDZ)]
is reported in the present study.
The data were then submitted to model-fitting and path
analysis.23 The models provided for additive
genetic variance (A) and variances attributable to shared or common
(C), nonshared or unique environmental factors (E), and phenotypic
interaction (P). The analyses included a
2 goodness-of-fit index, which tested the
agreement between the observed and the predicted statistics for the
models E, AE, CE, ACE, AEP, and ACEP. The various
parameters are expressed as an estimated percentage of the
total phenotypic variance and are termed h2,
c2, e2, and i2 for
heritability, common and unique environmental factors, and phenotypic
interaction, respectively. The final model was chosen as follows. If
the E model was fitting the data and no other model was significantly
better, then this simple model in which the observed variation is fully
explained by random environmental factors was accepted. The difference
between the 2 goodness-of-fit statistics
of two alternative models was tested by the difference in the
2 values, the degrees of freedom being the
difference between the degrees of freedom of the respective models.
First, the AE and CE models were compared with the E model. If only one
of these models was providing a better fit and if the more complex
models were not significantly better, then this two-component model
was accepted. If both models were fitting and significantly better than
the E model, then the ACE model was taken, provided that (1) it fit the
data; (2) the A and C estimates were both different from zero; and (3)
no other model was significantly better.
The analyses were performed on crude data and on residuals after adjustment for significant covariates, which were identified by regression analysis.
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Results |
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Characteristics of the Subjects
As shown in Table 1, age and weight were not significantly different between the monozygotic and dizygotic twins; however, the former were somewhat smaller. The AE model was the best-fitting model for height and for weight; genetic variance was estimated at 93% and 71%, respectively. Urinary sodium excretion was similar in both twin types, as were the intraclass correlation coefficients for this variable. The mean stress score and physical activity score, and the intraclass correlation coefficients of these estimates, were not associated with twin type. Monozygotic pairs were, however, more concordant than dizygotic pairs for actual sports activity (P<.01); this was confirmed by the significantly larger intraclass correlation coefficient for the weekly hours of sports activity in the monozygotic than in the dizygotic twins (P<.01). Smoking habits, alcohol consumption, marital status, and living conditions were not significantly associated with twin type.
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Blood Pressure: Means and Total Variances
Table 2 summarizes the means and the total
variances for the various systolic and diastolic
blood pressures. The group means for systolic pressure were
similar in the monozygotic and the dizygotic subjects, whereas the
diastolic 24-hour, awake, and crest pressures were
slightly, although significantly, higher in the dizygotic group. The
total variances of blood pressure were not significantly associated
with twin type.
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Blood Pressure: Genetic Analysis
With the exception of the 6-hour average afternoon pressure, the
intraclass correlation coefficients were higher in the monozygotic than
in the dizygotic twins, suggesting that the various blood pressures are
at least partly genetically determined. The heritability estimates
derived from these correlation coefficients were 69% for the
conventional systolic pressure, 63% for the 24-hour mean
pressure, 45% for the awake pressure, and 58% for the asleep
pressure; the estimates were similar for the crest and trough values
(Table 3). The heritability estimates
were somewhat lower for the diastolic pressures (Table 4).
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In the model-fitting and path analysis approach, models containing the A component in addition to the E component fit the data significantly better than the simple E model, as well for systolic and diastolic conventional pressures as for the various ambulatory pressure means. Genetic variance was greater than 50% for the various pressures, except for the negligible heritability estimate for the fixed 6-hour afternoon period. Most of the remaining variance could be attributed to unique nonshared environmental influences, with no or only slight contributions from the common environment, except for the afternoon blood pressure, which was determined by shared and nonshared environmental factors. Models that included phenotypic interaction were not significantly better than models without this factor.
Covariates of Blood Pressure
Systolic pressure was significantly and
consistently related to body weight (P<.01); the
correlation coefficients ranged from .30 to .37 for the various
pressures. Diastolic pressure was not related to weight,
except for the trough value (r=.22; P<.05).
There were no consistent relationships between nutritional and
lifestyle factors and the various blood pressures. The 24-hour urinary
sodium excretion, the weekly hours of sports activity, the weekly
alcohol consumption, and the daily number of cigarettes or cigars were
not significantly related to blood pressure, except for the positive
relationship between diastolic pressure during sleep and
alcohol consumption (r=.24; P<.05). Blood
pressure was not influenced by living conditions and marital
status.
The genetic analysis was repeated for the various systolic pressures after adjustment for weight. The heritability estimates from the model-fitting approach were 61% for conventional pressure, 64% for the 24-hour mean pressure, 55% and 50% for the awake and crest pressures, respectively, and 69% and 76% for the asleep and trough pressures, respectively. Blood pressure was not adjusted for other variables because their relations with the various pressure measurements were not consistent and only weak when significant.
Heart Rate
When measured during the physical examination, heart rate averaged
60 bpm in the monozygotic twins and 61 bpm in the dizygotic twins
(P=NS); the total variances, 201 and 143
bpm2, respectively, were not significantly different
between the twin groups. The heritability estimate according to Newman
was 41%; the model-fitting and path analysis approach did
not, however, yield an adequately fitting model (P=.06). The
24-hour mean heart rate and the averages during the awake and asleep
periods were significantly (P<.05) higher in the dizygotic
twins (73, 79, and 61 bpm, respectively) than in the monozygotic twins
(67, 73, and 57 bpm, respectively); the respective variances were not
different between the monozygotic twins (135, 172, and 113
bpm2, respectively) and the dizygotic twins (169,
193, and 181 bpm2, respectively). The heritability
estimates according to Newman were 58%, 51%, and 22%, for the
24-hour, awake, and asleep mean heart rates, respectively. The AE model
was the best-fitting model for each of these heart rates in the
model-fitting approach (.61<P<.90), in which
heritability was estimated at 70%, 65%, and 52%, respectively; the
remaining variance was attributed to unique environmental factors.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study confirms that blood pressure is significantly genetically determined.1 In the model-fitting approach, the genetic variance of conventional blood pressure was 64% of the estimated total variance for systolic and 73% for diastolic pressure. These relatively high estimates may be due to the fact that a rather homogeneous population of young male twins was studied. It has been shown that the influence of heritability decreases with advancing age and that the heritability estimates may be higher in men than in women.19 Furthermore, all blood pressures were measured by the same investigator and under well-standardized conditions: in the morning, in the same quiet room, and after the subjects had rested for 10 minutes in the supine position, which may have minimized environmental influences. In addition, the twin approach tends to overestimate heritability.22 Whereas similar environmental covariances are assumed for the monozygotic and dizygotic twins, environmental covariance may in fact be greater in the monozygotic twins.10 The questionnaire on lifestyle did, for example, reveal greater concordance for sports activity in the monozygotic twins. Although not significantly different between the twin groups, cohabitation, marital status, and alcohol consumption tended to be more similar in the monozygotic subjects. This may have biased upward the heritability estimates but may not have affected the comparison of the estimates for the various blood pressures, the major goal of the present study. It is reassuring, however, that Slattery et al10 found that the 60% and 66% heritability estimates for systolic and diastolic blood pressures, respectively, were not altered by adjustment for dietary intake, smoking, alcohol and caffeine consumption, fatness, and physical activity and fitness, despite the greater lifestyle concordance in the monozygotic twins. Few other twin studies have applied similar statistical methods to quantitate the effect of genes on the level of conventional blood pressure. Univariate genetic analysis revealed that genetic effects accounted for 66% of the variance of systolic pressure and for 64% of the variance of diastolic pressure in 11-year-old boys, and these estimates were 66% and 51%, respectively, in girls.11 In 17- to 65-year-old adults, genetic variance of diastolic pressure was 52% in men and 43% in women; there was no indication of sex heterogeneity for systolic pressure, for which the overall heritability estimate was 60%.15 Bielen et al12 studied 18- to 31-year-old male twins and found heritability estimates of 69% for systolic and 32% for diastolic pressure, respectively. Results from twin studies that used model-fitting techniques agree therefore that conventional blood pressure is under partial genetic control.
In the present study, ambulatory blood pressure was measured during the subjects' usual activities. The mean pressure values were very similar to those measured in a population sample of 20- to 49-year-old healthy men in a small Flemish town, in whom mean 24-hour, daytime, and nighttime pressures averaged 121/72, 126/77, and 110/62 mm Hg, respectively.28 The genetic variance of the average 24-hour blood pressure amounted to 70% for systolic and 73% for diastolic pressure. In a further step of the analysis, daytime and nighttime measurements were considered separately. When the daytime pressure was taken as the average pressure for the total awake period (ie, when the subjects were out of bed), genetic variance was 63% and 55% for systolic and diastolic pressures, respectively. The results were similar when the daytime pressure was derived from cusum analysis26 and defined as the highest average pressure during any consecutive 6-hour period (crest). By contrast, the average blood pressure during the fixed 6-hour period from 2 PM to 8 PM was determined by shared and nonshared environmental factors. A possible explanation for these apparent discrepancies is the fact that the individual subjects' activities may have been quite different during the studied afternoon period but that the sum of activities during the total awake period and during the 6 hours with the highest pressure were rather similar. Furthermore, the effect of various daytime activities on the heritability estimates of blood pressure is not consistent. Whereas dynamic and isometric physical activities seem to reduce the estimates,4 12 genetic variance is maintained for the blood pressure response to mental activity.7 9 13 Both the total period that the subjects were in bed (asleep) and the 6-hour period with the lowest blood pressure (trough) showed significant heritability. The genetic variance for systolic pressure, 72% and 77%, respectively, was somewhat higher than the estimates for the total awake period and the crest value, but the statistical approach used does not allow us to assess the significance of these differences. Daytime and nighttime estimates were indistinguishable for diastolic pressure. In general, heritability estimates of the various ambulatory blood pressure means were similar to the estimates for the standardized conventional pressure, except for the fixed afternoon period.
Degaute et al18 recently reported on 24-hour blood pressure in a similar population of young male twins. They restricted their genetic analysis to the methodology described by Christian22 and did not apply model fitting, so that only the reported intraclass correlation coefficients can be compared with our results. Whereas our study showed significant genetic variance for systolic and diastolic 24-hour pressures, Degaute et al agree for diastolic but not for systolic pressure, for which they observed an exclusive environmental effect. This was primarily because of the predominant environmental influence on the mean sleep values, whereas we found that the heritability of the sleep pressure was similar to the heritability of the awake pressure, or even somewhat superior. A major difference between the studies is that ambulatory blood pressure was recorded in the twins' usual environment in our study, whereas Degaute et al admitted the subjects to the hospital; they spent the night in a sleep laboratory, where, in addition, polygraphic sleep recordings were performed. Despite habituation to the procedures, blood pressure during sleep may be environmentally influenced under such conditions but less so when the subjects sleep in their natural environment.
The various systolic but not diastolic pressures were significantly related to weight, which is itself under partial genetic control. The univariate heritability estimate may have included the effect of genes that control an aspect of both blood pressure regulation and weight. The slight reduction of the heritability estimates after adjustment of blood pressure for weight suggests that only a small part of the genetic variance of systolic pressure is related to such shared genes.
In addition to the assessment of inheritance, the model-fitting and path analysis approach used in the present study allowed for phenotypic interaction and for shared and nonshared environmental effects. Fitting models that included phenotypic interaction were not significantly better than models without this factor, suggesting that there were no appreciable mutual influences on blood pressure within the twin pairs. For most blood pressures, the variance that could not be explained by genetic factors could be attributed to unique nonshared environmental influences, with no or only small contributions of the common environment, in agreement with other reports on conventional blood pressure.4 11 12 15 16 17 Only the mean 6-hour afternoon blood pressure was under the influence of both shared and nonshared environmental factors.
Several8 11 12 29 but not all13 reports agree that resting heart rate, measured during physical examination or derived from the electrocardiogram, is under partial genetic control. There was no adequately fitting model for resting heart rate in the present study, but fitting models were obtained for ambulatory heart rate. The results have to be interpreted with caution, however, because of the consistently higher heart rate in the dizygotic than in the monozygotic twins. The heritability estimate was significant and amounted to 70%, 65%, and 52% for the 24-hour mean and the averages during the awake and asleep periods, respectively. Degaute et al18 noted a trend for a genetic effect for the 24-hour and the daytime mean heart rates and an environmental effect for heart rate during sleep. As for blood pressure, the finding of a genetic effect on nighttime heart rate in our study but not in the report by Degaute et al18 could be due to the different environmental conditions, as described above.
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Acknowledgments |
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The study was supported by the National Fund for Medical Research NFWO, Brussels, Belgium. The authors gratefully acknowledge the secretarial assistance of Nicole Ausseloos and Yvette Toremans and the logistic assistance of Fabienne Cormenier.
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Footnotes |
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Reprint requests to R. Fagard, MD, PhD, UZ Pellenberg, University of Leuven, Weligerveld 1, B-3212 Lubbeek (Pellenberg), Belgium.
Received March 13, 1995; first decision April 24, 1995; accepted July 21, 1995.
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