Published online before print May 21, 2007, doi: 10.1161/CIRCULATIONAHA.106.674812
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(Circulation. 2007;115:2931-2938.)
© 2007 American Heart Association, Inc.
Hypertension |
Genetic and Shared Environmental Factors Do Not Confound the Association Between Birth Weight and Hypertension
A Study Among Swedish Twins
From the Department of Medical Epidemiology and Biostatistics (N.B., A.I., S.J., Y.P., N.L.P., P.L., S.C.), Division of Cardiovascular Epidemiology, Institute of Environmental Medicine and Department of Cardiology, Karolinska University Hospital (U.d.F.), Karolinska Institutet, Stockholm, Sweden, and Departments of Pediatrics and of Epidemiology and Biostatistics, McGill University Faculty of Medicine, Montreal, Canada (M.S.K.).
Correspondence to Niklas Bergvall, MSc, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, PO Box 281, SE–171 77 Stockholm, Sweden. E-mail niklas.bergvall{at}ki.se
Received November 7, 2006; accepted March 30, 2007.
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Abstract |
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Background— Studies have found associations between low birth weight and increased risks of cardiovascular diseases in adulthood. However, these associations could be due to confounding by genetic or socioeconomic factors.
Methods and Results— We performed a study on Swedish like-sexed twins with known zygosity who were born from 1926 to 1958. First, to obtain an overall effect of birth weight on risk of hypertension, we performed cohort analyses on all twins (n=16 265). Second, to address genetic and shared environmental confounding, we performed a nested co-twin control analysis within 594 dizygotic and 250 monozygotic twin pairs discordant for hypertension. Birth characteristics, including birth weight, were obtained from original birth records. Information from adulthood was collected from a postal questionnaire in 1973 (body mass index, height, smoking, and alcohol use) and from a telephone interview conducted from 1998 to 2002 (hypertension and socioeconomic status). Hypertension was defined as reporting both high blood pressure and treatment with antihypertensive medication. In the cohort analysis, the adjusted odds ratio for hypertension in relation to a 500-g decrease in birth weight was 1.42 (95% confidence interval, 1.25 to 1.61). In the co-twin control analyses, the corresponding odds ratios were 1.34 (95% confidence interval, 1.07 to 1.69) for dizygotic and 1.74 (95% confidence interval, 1.13 to 2.70) for monozygotic twins.
Conclusions— In the largest twin study on the fetal origins of hypertension, we found that decreased birth weight is associated with increased risk of hypertension independently of genetic factors, shared familial environment, and risk factors for hypertension in adulthood, including body mass index.
Key Words: hypertension • birth weight • twins
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Introduction |
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Numerous studies have reported associations between measures of fetal growth restriction and increased risks of cardiovascular diseases later in life.1 It has been suggested that restricted fetal growth may reflect insufficient energy supply for organ development, which in turn may increase disease susceptibility later in life.2 However, it also has been argued that the association may be confounded by socioeconomic and genetic factors.3,4
Clinical Perspective p 2938
Twin studies provide opportunities to study the association between fetal growth and hypertension, controlling for shared (familial) environmental and genetic factors.5 Twin siblings share genes (half if dizygotic and all if monozygotic), intrauterine exposures, maternal factors, and early environment. Furthermore, twin siblings often differ in birth weight.6 Because twin siblings have identical gestational age, differences in birth weight within twin pairs reflect differences in fetal growth.
We analyzed prospectively collected information on birth characteristics on 16 265 Swedish like-sexed twins with known zygosity to investigate whether the association between birth weight and hypertension is confounded by shared (familial) environmental or genetic factors.
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Methods |
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Study Population
Eligible participants in the present study were like-sexed twins born in Sweden from 1926 to 1958, who are included in the Swedish Twin Registry (n=37 392).7 In 1973, 30 305 twins (81%) from intact pairs and residing in Sweden responded to a postal questionnaire on health and lifestyle habits. In 1998, twins born in 1958 or earlier who were alive and residing in Sweden were invited to participate in a telephone interview called the Screening Across the Lifespan Twin (SALT) Study.8 Among the 32 905 like-sexed twins born from 1926 to 1958 invited to participate in SALT (regardless of their participation in the 1973 questionnaire), the response rate was 74% (n=24 295). Nonresponse was due largely to refusal (55%) and inability to make contact (39%). In this study, we restricted the cohort to twins with known zygosity (n=23 547), as determined by questions on childhood resemblance. Self-reported zygosity has been validated with DNA markers in a subsample of 199 twin pairs and was proved correct in 99% of the twin pairs.7 Among the 23 547 individuals in the defined study population, 21 125 (90%) had previously responded to the postal questionnaire in 1973.
Outcome
In SALT, all participating twins were asked questions about their medical history and current use of prescription medications.7 In the present study, individuals were diagnosed with hypertension if they answered yes to both of the following 2 questions: "Do you have or have you had high blood pressure?" (question 1) and "Do you take any medication daily?" (question 2) and named an antihypertensive drug. An antihypertensive drug was identified as a medication having an Anatomic Therapeutic Chemical Classification System code of C02, C03, C07, C08, or C09 and being listed in the Swedish Drug Compendium during the years 1997 to 2002.9 An individual was classified as nonhypertensive if he or she answered "no" to question 1 and, when asked question 2, either stated that he or she did not take prescription medications or reported medications that were not listed as antihypertensive drugs.
In the defined study population, 3232 (13.7%) were classified as having hypertension, 17 381 (73.8%) as nonhypertensive, and 2934 (12.5%) as nonclassifiable. Among those not classified, 29.4% reported a hypertensive medication in question 2 but answered "no" to question 1, 64.8% answered yes to question 1 but did not name a hypertensive medication in question 2, and 5.8% did not answer both questions. To test the sensitivity of our definition of hypertension, we included in additional analyses those who reported hypertension but not use of antihypertensive drugs as hypertensive (64.8% of those originally assessed as being nonclassifiable).
Exposures
Information about maternal and birth characteristics is routinely documented at birth by the attending midwife, and birth records are kept at local delivery archives throughout Sweden. The recording of information on birth records and the preservation of these records are required by law. Correct birth identification of each twin within a pair was ensured by restriction to twin pairs who were both baptized and named at birth or who agreed on birth order in SALT. Information about birth order was validated in a sample of 2713 like-sexed twin pairs who were both baptized at birth and responded to the question on birth order in SALT. A 95% agreement existed between birth order as stated in SALT and in the birth records. For the 23 547 like-sexed twins with known zygosity, medical birth records, with correct identification of individual twins, were obtained for 18 572 (79%) individuals, among whom 16 265 (in 5791 complete twin pairs) had information both on birth weight and hypertension in adulthood.
Information on parental socioeconomic status (SES) and obstetric and birth characteristics was collected from original medical birth records. Gestational age was based on date of the last menstrual period. SES was classified according to recommendations by Statistics Sweden.10 SES at birth was defined as the highest SES of the parents using information from mothers’ and fathers’ occupations. SES in adulthood was based on self-report of occupation in the SALT interview. Those currently employed were asked what occupation they had during the last 12 months; those not currently employed were asked what their last occupation was; and retirees were asked about their primary occupation in adulthood. Information on adult weight, height, smoking, and alcohol consumption was collected through the 1973 postal questionnaire. Body mass index (BMI) was calculated as the ratio between weight and squared height (kg/m2). Smoking status was dichotomized into those who had ever smoked (current and previous smokers) and those who had never smoked. Alcohol consumption was classified according to recommendations by the World Health Organization as low consumption (women, 0 to 19 g alcohol/d; men, 0 to 39 g alcohol/d), medium consumption (women, 20 to 39 g alcohol/d; men, 40 to 59 g alcohol/d), and high consumption (women, >40 g alcohol/d; men, >60 g alcohol/d).11
Statistical Methods
The association between birth weight and hypertension was initially analyzed in the twin cohort, including 16 265 twins with information on birth weight and hypertension. Generalized linear mixed models were used to correct for the fact that we have correlated data, with random intercepts that vary from pair to pair and assuming a logit link function fitted with PROC NLMIXED (SAS Institute, Cary, NC).
The effect of birth weight on risk of hypertension, controlling for common genetic and shared environmental factors, was estimated in a nested co-twin control analysis.12 To infer confounding by genetic and shared environmental factors on the association between birth weight and hypertension, the co-twin control analysis was stratified by zygosity. Whereas the cohort analysis uses the entire cohort of twins, the co-twin control analysis was restricted to the 594 dizygotic and 250 monozygotic twin pairs discordant for hypertension. The paired effects in the co-twin control analysis were estimated by conditional logistic regression in SAS with PROC PHREG.
In the co-twin control analysis, healthy co-twins were used as matched controls for the cases. Because twins share intrauterine exposures, maternal factors, 50% (dizygotic) or 100% (monozygotic) of their segregating genes, and generally childhood and adolescent environment (97% of the twins responded that they lived with their co-twin until 15 years of age), the matched nature of the co-twin control design minimizes confounding by these factors. If the estimated paired effects are smaller than the effect seen in the cohort or null, the association between birth weight and hypertension in the cohort analysis is probably confounded by factors shared by co-twins. Because dizygotic twins share on average 50% of their segregating genes, the estimated paired effect of birth weight on risk of hypertension in dizygotic twins only partly accounts for confounding by shared genetic factors, which are fully controlled for in monozygotic twins. Thus, if the paired effect of birth weight on risk of hypertension is smaller in monozygotic than in dizygotic twins, the association is confounded by genetic factors. If the paired effect is similar in monozygotic and dizygotic twins but smaller than the cohort effect, the association is confounded by shared environmental factors.
The study was approved by the research ethics committee of the Karolinska Institutet. The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Rates of hypertension by birth, maternal, parental, and adult characteristics are shown in Table 1
. Rates of hypertension were substantially influenced by year of birth, and women had higher rates of hypertension than men. Rates of hypertension consistently decreased with increasing birth weight, and the highest rate was found among individuals born with low birth weight (
1999 g). More than half of the twins who were obese (BMI 
30.0 kg/m2) in 1973 had hypertension in 1998 to 2002. Rates of hypertension were higher among twins born to parents with low SES than among those born to parents with higher SES. Similarly, twins with low SES in adulthood had higher rates of hypertension. Smokers and high alcohol consumers in 1973 had higher rates of hypertension compared with nonsmokers and low alcohol consumers. Those lacking information on gestational age and parental SES were, at the time hypertension was diagnosed, 3 and 7 years older than those with information. In addition, those lacking information on gestational age had 116-g-lower mean birth weight than those with information.
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Table 2 displays frequencies of hypertension among twins with lower versus higher birth weight in a twin pair in relation to risk factors of hypertension in adulthood. In contrast to genetic, maternal, and shared environmental factors, risk factors in adulthood cannot be controlled for by design. By assessing differences in the distribution of such risk factors, we sought to see whether such risk factors were found more often among twins born with low birth weight compared with those with high birth weight. Risk factors in adulthood generally were associated with rates of hypertension among those with both lower and higher birth weight in a pair. However, only height and SES were distributed differently between the 2 birth weight groups (P=0.01 and 0.02, respectively); those with lower birth weight in a pair tended to be shorter and were more likely to be blue-collar workers in adulthood, factors that were associated with increased rates of hypertension.
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Table 3 shows unadjusted and adjusted odds ratios (ORs) from the cohort analysis of birth weight and risk of hypertension. The risk of hypertension increased with decreasing birth weight. Using birth weight as a continuous variable, we found that a 500-g decrease was associated with a 24% increase in risk of hypertension in the unadjusted model and 42% in the fully adjusted model. However, the models had varying sample sizes as a result of missing information on covariates. We therefore also restricted all the models to subjects without missing values on any covariates (n=9294). Adjusting for covariates did not substantially alter the association between birth weight and risk of hypertension. No significant interactions were found between birth weight and birth year, sex, or any of the risk factors for hypertension in adulthood (data available on request).
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Table 4 displays the results from the co-twin control analyses of the association between birth weight and risk of hypertension stratified by zygosity. The "unadjusted model" in a co-twin control analysis (by default) controls for all factors shared by the twins. Among both dizygotic and monozygotic twins, rates of low birth weight (1999 g) were higher among cases compared with their healthy co-twin controls. Among dizygotic twins, a 500-g difference in birth weight within a twin pair was associated with a 34% increased risk of hypertension in the adjusted analysis. Contrary to the hypothesis of genetic confounding, we found that a 500-g difference in birth weight within monozygotic pairs was associated with a 74% increased risk of hypertension. To confirm our interpretation of the effect of adjustment for selected covariates, we fitted an unadjusted model that was based on the same sample as that used in the adjusted model. Within both dizygotic and monozygotic twin pairs, we found similar estimates in the unadjusted and adjusted models, indicating that the included risk factors for hypertension did not confound the association between birth weight and risk of hypertension.
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Finally, we repeated the cohort and co-twin control analysis after reclassifying those subjects who reported hypertension but not antihypertensive medication as being hypertensive instead of nonclassifiable. Including the additional hypertensive twins attenuated the effect of a 500-g decrease in birth weight on risk for hypertension, both in the cohort analysis (fully adjusted model: OR, 1.28; 95% confidence interval [CI], 1.17 to 1.40) and within dizygotic and monozygotic twins in the co-twin control analysis (adjusted OR, 1.16; 95% CI, 0.98 to 1.38; and adjusted OR, 1.24; 95% CI, 0.95 to 1.62, respectively).
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Discussion |
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We found that the risk of hypertension increased with reduced birth weight both in a cohort of twins and within dizygotic and monozygotic twin pairs. Thus, our results, based on the largest twin study to date, support the hypothesis that fetal growth per se influences the risk of hypertension later in life.
Twin studies provide control for environmental and genetic factors shared by twins. A recent meta-analysis of twin studies supported the possibility that factors shared by twins confound the association between birth weight and blood pressure.4 However, no convincing evidence was found to support genetic, as opposed to shared environmental, confounding. In contrast to studies on twins, studies of full siblings found stronger relationships between birth weight and blood pressure within than between families, arguing that factors that are fixed between consecutive pregnancies, including maternal genotype, do not confound the association.13,14 Sibling studies provide control for familial (genetic and shared environmental) factors. However, full siblings share only half of their genes, and maternal factors and intrauterine environment may differ between siblings.
Differences between our results and those reported in previous twin studies may be partly attributable to differences in sample size and definition of outcome. A meta-analysis of twin studies included 7336 twins with known zygosity from 10 studies,4 whereas our study included 9731 dizygotic (3332 twin pairs and 3067 single twins) and 6534 monozygotic (2459 twin pairs and 1616 single twins) twins, of whom 594 dizygotic and 250 monozygotic twin pairs were discordant for hypertension. All twin studies included in the meta-analysis compared mean blood pressure measurements among young and middle-aged individuals, whereas the present study included middle-aged and elderly twins with hypertension.
In addition to the large sample size, our study also benefits from several other strengths. Information on perinatal and parental sociodemographic characteristics was retrieved from original birth records, and data on exposures in adulthood, except SES, were collected at least 25 years before ascertainment of the outcome (hypertension). Our exposure and covariate information should preclude recall bias.
The prevalence of self-reported hypertension in our study population (23%) is lower than the prevalence of hypertension for the Swedish population with the same age distribution (34%).15 The primary cause of the low prevalence of hypertension in our study is likely the fact that some hypertensive individuals were incorrectly classified as not having hypertension. The sensitivity of self-reported hypertension is low (ranging from 43% to 82%), whereas the specificity is reported to be high (ranging from 80% to 95%).16 Women are up to twice as likely to correctly report hypertension as men,16 which may explain the obtained increased rate of hypertension among women compared with men. In the present study, we used, in addition to self-reported high blood pressure, daily use of antihypertensive prescription drugs as a prerequisite to be classified as having hypertension. This resulted in a prevalence of hypertension of 16%, but rates of hypertension increased as expected with increasing age, BMI, smoking, and high alcohol consumption. Given the high specificity and probably low sensitivity of the diagnosis of hypertension in our study and assuming nondifferential misclassification, we have, if anything, underestimated the effect of birth weight on hypertension.16
When we also included those subjects who reported hypertension but not antihypertensive medication as having hypertension, the association between birth weight and hypertension was attenuated. Nevertheless, birth weight was still significantly associated with hypertension in the cohort analysis. In the co-twin control analyses, risks within monozygotic twin pairs, although slightly attenuated relative to those found in the entire cohort, were larger than within dizygotic pairs, implying that genetic factors do not confound the association. We speculate that the attenuation of risk is due to the following 2 causes. First, some of those reporting hypertension but not antihypertensive medication may have falsely reported hypertension and thus diluted the hypertensive group with nonhypertensive individuals. Second, a recent Swedish study found that the willingness of doctors to initiate or give further antihypertensive drug treatment increased with severity of hypertension.17 Thus, those reporting hypertension but not antihypertensive medication may have a milder form of hypertension than those also reporting antihypertensive medication and hence a weaker association with birth weight.
The appropriateness of adjusting for BMI when studying associations between birth weight and cardiovascular diseases later in life has been questioned.18 However, in the present study, we found no evidence that BMI or other factors in adulthood influenced the association between birth weight and hypertension.
Twin studies may be considered almost ideal in studying associations between fetal growth and subsequent risks of cardiovascular diseases. First, analyses taking zygosity into account allow for varying degrees of control for genetic factors.5 Second, twins are generally brought up together, and analyses within twin pairs provide control for unmeasured environmental and socioeconomic factors during childhood.5 Third, differences in birth weight within twin pairs reflect differences in fetal growth.
Generalizability of our findings in twins to the general population may be a concern. Because twins generally are more growth restricted in utero than singletons,19 they may have higher rates of coronary heart disease and hypertension later in life. However, twins do not differ from singletons with respect to risk of cardiovascular mortality and blood pressure.20,21 In our cohort analyses, results were consistent with those previously reported in unrelated singletons.22 In the co-twin control analyses, we found that the association between birth weight and hypertension was not confounded by genetic or shared environmental factors. If anything, our results indicate that the effect of birth weight differences on risk of hypertension is stronger within monozygotic than dizygotic twins, indicating that the association may well be explained by factors affecting fetal nutrition and growth.
As with singletons, birth weights of twins are influenced by environmental insults and genetic and placental factors. The fetal origins of adult diseases hypothesis states that fetal malnutrition during the third trimester increases the risk of cardiovascular diseases later in life.2 Although weight gain during the third trimester is less pronounced among twins compared with singletons,19 intertwin disparity in fetal size within twin pairs increases with gestation.23
All dizygotic twins and a third of monozygotic twins are dichorionic (ie, they have separate placentas). In dichorionic twins, discordant fetal growth is related to both differences in genetic influences (dizygotic twins) and placental factors (dizygotic and monozygotic twins).24,25 Monochorionic twins share placentas and are always monozygotic. In monochorionic twins, discordant fetal growth is related to the vascular architecture of the shared placenta, including umbilical cord insertions.26,27 A recent study found that unequal placental sharing appears to be the primary contributor to birth weight discordance in monochorionic twin pairs.28 Thus, birth weight discordance within dizygotic and monozygotic twins is related mainly to placental factors that influence fetal nutrition. We cannot see any major differences in being subjected to inadequate placental nutrition between monozygotic twins, dizygotic twins, or singletons.
It has been proposed that the fetus, in response to undernutrition in utero, makes physiological adaptations that may be beneficial in the short term but may lead to increased risk of hypertension later in life.1 Influences on organs and mechanisms regulating blood pressure during the prenatal period have been studied as potential mechanisms for the fetal origins of hypertension. One proposed mechanism is alterations in the structure and function of the kidney, leading to reduced numbers of nephrons and resulting glomerular hyperfiltration.29 Others have proposed structural changes in the vasculature tree, leading to impaired endothelial function and arterial stiffness, as a potential mechanism.30 Most studies of mechanisms behind fetal origins of hypertension, however, have focused on fetal exposure to glucocorticoids.31 Excessive prenatal exposure to glucocorticoids is deemed important in the programming of hypertension in that it is both growth inhibitory32 and suggested to be a common cause of many structural and physiological changes related to regulation of blood pressure, including low nephron number,29 activation of the renin angiotensin system,33 and alterations in the hypothalamic-pituitary-adrenal axis.34
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Conclusion |
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Whatever the underlying mechanisms, our findings suggest that the association between fetal growth and hypertension is independent of genetic factors and environmental factors during childhood and adulthood.
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Acknowledgments |
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Sources of Funding
The study was supported by grants from the Swedish Heart and Lung Foundation (grants 2001/4126 and 2002/0324), the Swedish Cancer Society (grants 4594-B01–01XAC and 4594-B04–04XAB), the Swedish Council for Working Life and Social Research (grant 2004–0174 and Dnr 2004–1654), the Swedish Research Council (grants K2003–71X–14676–01A and K2006–71X–14676–04–2), the Fonds de la recherche en santé du Québec, and the European Union–funded Network of Excellence LifeSpan (FP6 036894).
Disclosures
None.
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