Genetic and environmental origins of the association between birth weight and cardiovascular risk factors

The fetal origins hypothesis suggests that the association between birth weight and cardiovascular risk is due to a programed response to intrauterinemalnutrition [1]. According to this hypothesis, improvements in intrauterine nutrition may prevent cardiovascular disease in later life. This would have major implications for public health. However, both birth weight and cardiovascular disease are influenced by genetic factors. Therefore, the alternative view is that genetic factors influencing both birth weight and adult disease are responsible for the association [2]. In other words, a genotype responsible for cardiovascular disease in later life may cause retarded fetal growth in utero. In this case, nutrition-induced improvements in fetal growth may not prevent the development of cardiovascular disease. To distinguish between environmental and genetic influences, mechanistic tests of the fetal origins hypothesis are required. Only in experimental settings can we investigate whether the association of one variable with another is causal. An ideal experimental setting creates circumstances across which only one factor affecting the outcome of interest varies. Numerous experiments in sheep and rats have shown that maternal undernutrition during pregnancy is related to disease in the offspring [3]. However, is not known whether the results from animal studies can be extrapolated to humans. In humans, an experimental setting is usually achieved in a randomized trial. However, a randomized trial in humans with interventions to influence birth weight is almost impossible to perform. Usually, the term experiment is restricted to situations in which circumstances are manipulated by the investigator. However, intrapair comparisons in twins provide a unique opportunity to mimic a scientific experiment. The influence of one factor (in this case birth weight) on the outcome of interest (cardiovascular risk factors) can be investigated independent of many other factors (such as genetic factors), because the influence of these factors is eliminated within pairs. Therefore, twins can be considered as an experiment of nature . Twin pairs provide a unique tool to investigate the influence of genetic factors. In monozygotic twins, who are genetically identical, the influence of genetic factors on the differences within a twin pair is excluded. In dizygotic twins, who share on average half of their genes, the influence of genetic factors is reduced, but not excluded. If genetic factors do not play a role in the association between birth weight and cardiovascular risk factors, one would expect that, both for dizygotic and for monozygotic twins, the twin with the lowest birth weight from each pair will also have the highest level of the cardiovascular risk factor compared with the co-twin with the highest birth weight. In addition, inverse associations between intrapair differences in birth weight and intrapair differences in the risk factor should exist both in dizygotic and in monozygotic twins. If, however, genetic factors do play a role, these associations would exist only within dizygotic twins, and not within monozygotic twins. In this case, within dizygotic twins, unfavorable genetic factors will cause growth retardation and cardiovascular disease in one twin, but not in the co-twin who does not have the unfavorable genotype. Inmonozygotic twins, both twin members have the same genotype, so they both have the same unfavorable or favorable genetic factors. Several twin studies have shown that the association between low birth weight and high blood pressure was present within dizygotic twins, but absent in monozygotic twins, suggesting that genetic factors are important [4–6]. However, twin studies investigating the association between birth weight and glucose metabolism have shown that this association is present within the dizygotic as well as within the monozygotic twin pairs [7–9]. This provides evidence for an intrauterine environmental cause of the relationship between low birth weight and diabetes. Several studies in singletons have demonstrated associations between low birth weight and increased plasma concentrations Correspondence: R. G. Ijzerman, Department of Internal Medicine and Institute for Cardiovascular Research, VU University Medical Center, Vrije Universiteit, Amsterdam, The Netherlands. Tel. : +31 20 44 40629; fax: +31 20 44 44313; e-mail: rg.ijzerman@ vumc.nl Journal of Thrombosis and Haemostasis, 3: 1141–1142