College of Medicine and Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK
* Corresponding author. E-mail: g.mcneill{at}abdn.ac.uk
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Abstract |
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Methods A systematic review identified 10 studies covering 3901 twin pairs. Meta-analysis of regression coefficients for the association between birthweight and systolic blood pressure was carried out for unpaired versus paired associations and for paired associations in dizygotic versus monozygotic pairs.
Results After adjustment for current weight or body mass index (BMI), the difference in systolic blood pressure per kg birthweight was 2.0 (95% CI: 3.2, 0.8) mmHg in the unpaired analysis and 0.4 (95% CI: 1.5, 0.7) mmHg in the paired analysis in the same subjects. In the paired analysis by zygosity, in all twins the coefficients were 0.7 (95% CI: 2.3, 0.8) mmHg in dizygotic pairs and 0.8 (95% CI: 2.1, 0.4) mmHg in monozygotic pairs, but in studies which included zygosity tests the coefficients were 1.0 (95% CI: 3.3, 1.6) mmHg in dizygotic pairs and 0.4 (95% CI: 1.9, 1.3) mmHg in monozygotic pairs.
Conclusions The attenuation of the regression coefficient in the paired analysis provides support for the possibility that factors shared by twins contribute to the association between birthweight and blood pressure in singletons. Comparison of paired analysis in monozygotic and dizygotic pairs could not provide conclusive evidence for a role for genetic as opposed to shared environmental factors.
Accepted 18 May 2004
The fetal origins hypothesis proposed by Barker and colleagues suggests that birthweight is inversely associated with risk of cardiovascular and other metabolic disease in adult life through a long-term effect of sub-optimal intra-uterine nutrition on later metabolism.1 Others have suggested that the observed association may result from unmeasured socio-economic confounding2 or genetic or other inter-generational factors influencing both birthweight and adult disease risk.3,4 Twin studies provide an opportunity to test these alternative possibilities, since twins share their maternal and early family environment and some or all of their genes but often differ considerably in birthweight. If the association between birthweight and disease risk seen in singletons can be reproduced in twins when treated as a population of individuals, or unpaired twins and is also seen in analyses within twin pairs, the influence of genetic or family environment on the association is likely to be small. If however the association is seen in unpaired twins but is attenuated in paired analyses, genetic factors and/or family environment are likely to play a role in the association. Furthermore, since dizygotic (DZ) pairs share half of their genes but monozygotic (MZ) pairs share all their genes, partial attenuation in DZ pairs and total attenuation in MZ pairs would provide evidence for a role of genetic factors as opposed to other shared family environment influences.
Early studies of the association between birthweight and systolic blood pressure in singletons suggested an effect of the order of 5 mmHg per kg birthweight,5,6 but more recent systematic reviews have suggested that the effect size is considerably smaller.79 One of these reviews included a meta-analysis of data from MZ pairs from nine twin studies and found a similar effect size to that found in larger studies of singletons,9 which would be consistent with a lack of effect of genetic factors and socio-economic environment in childhood on the observed association in singletons. However, these authors did not explore the unpaired data or data from DZ pairs in the twin studies. We therefore carried out meta-analyses of published twin studies to permit the comparison of unpaired versus paired results and the comparison of MZ versus DZ twins. We also analysed the data before and after exclusion of studies which used self-reported rather than obstetric or midwives' records of birthweight and studies which did not include zygosity tests to investigate the possible impact of errors in birthweight and zygosity in these studies.
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Materials and Methods |
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Results |
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Discussion |
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The attenuation of the regression coefficients between unpaired and paired analyses in the twins suggests that factors which are common to twins in a pair contribute to the observed association in singletons. The degree of attenuation in DZ versus MZ pairs is more difficult to interpret, as in the paired analyses of all studies there was no difference in the regression coefficients between DZ and MZ pairs, suggesting that shared environmental factors such as maternal physiology or socio-economic conditions in early childhood are more likely to explain the attenuation, but restricting the analysis to studies with zygosity tests gave lower coefficients in MZ than DZ pairs, as would be expected if genetic factors contributed to the association. Lower coefficients in MZ than DZ pairs were also observed when the analysis was restricted to studies which used obstetric or midwives' records of birthweight. The importance of these possible sources of error is difficult to assess as it is likely to differ between study populations and probably differs between singletons and twins. One study of the accuracy of self-reported birthweight in 302 adult twins found that the mean agreement between self-reported weight and birth records was 6.2 g but the 95% CI ranged from 660 to +672 g, and for the 139 pairs in the survey the mean agreement for birthweight difference was 224 g but the 95% CI ranged from 863 to +815 g.20 For zygosity the possibility of errors due to incorrectly assignation of zygosity is highlighted by a recent US study of adolescent same-sex twins which found that 26% of mothers who received DNA results by mail changed their opinions of the twins' zygosity, while 22% of those who did not receive DNA result also altered their opinions on a second questionnaire.21 In our own study population most mothers had been sent information on zygosity after birth, based on either blood groups or DNA fingerprinting, but at age 1950 years 5% of twins said they were not sure of their zygosity and a further 8% reported zygosity which did not agree with the results of DNA fingerprinting.
Another factor which could attenuate the association between birthweight differences and adult risk factors in twins compared to singletons is cross over of birthweights due to errors in recall of birth order and hence birthweight, which is usually recorded by birth order, within a twin pair. This would lead to attenuation of the associations in both unpaired and paired analyses, though the effect would be possibly be greater in the paired analyses due to reversal of the direction of within-pair differences in birthweight. One study attempted to address this issue by using discrepancies between self-reported birth order and that recorded on a birth register to exclude pairs in which this effect was considered likely.18 Although the regression coefficients in this study were not obviously different from other studies, this is a potential source of error which should be borne in mind in all twin studies of birthweight.
One possible criticism of the use of MZ pairs is that two-thirds of MZ pregnancies are monochorionic and in these pregnancies twin-twin transfusion syndrome may result in birthweight discordance and blood pressure differences through mechanisms not experienced by singletons.22 Although a recent study found no difference in within-pair differences in birthweight between monochorionic and dichorionic twins,23 the results from the DZ pairs may be considered more reliable as they cannot be influenced by twin-twin transfusion syndrome. An alternative approach would be to present results separately for monochorionic and dichorionic MZ pairs: we tried to do this in our own study by examining obstetric case notes but diagrams of the membranes were only found for 29 of the 60 MZ pairs.
Although the present analysis covers almost 4000 twin pairs, several limitations of the data are apparent. Unadjusted and unpaired coefficients were not given by all studies, though they were available for the two largest studies14,18 and the trends were consistent among the studies for which these results were given. Of the five studies which presented unpaired data only two reported using methods to account for the pairing within this data.14,17 As pointed out by the authors of one of these studies,14 failure to do so will lead to underestimation of the standard errors of the coefficients, which in their study was of the order of 20%, so the CI for unpaired analyses in Table 3 and Figure 1 should be viewed in this light.
In summary, the evidence from published twin studies lends support to the possibility that factors shared by twins contribute to the association between birthweight and blood pressure in singletons. While the comparison of DZ versus MZ pairs in twins of confirmed zygosity in the current analysis is consistent with a role for genetic as opposed to environmental factors, the small effect size in the paired analysis means that much larger studies would be needed to provide a definitive test of the difference between the two values. For other variables associated with the metabolic syndrome such as glucose intolerance and lipid levels, the twin approach could be of greater value in assessing the relative contribution of genetic and environmental factors to the associations seen in singletons.
KEY MESSAGES
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Acknowledgments |
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References |
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