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

Abstract

The fetal origins hypothesis suggests that the association between birth weight and cardiovascular risk is due to a programed response to intrauterine malnutrition [1Barker D.J. Mothers, Babies and Health in Later Life. Churchill Livingstone, 1998Google Scholar]. 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 [2Hattersley A.T. Tooke J.E. The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease.Lancet. 1999; 353: 1789-92Abstract Full Text Full Text PDF PubMed Scopus (740) Google Scholar]. 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 [3Hoet J.J. Hanson M.A. Intrauterine nutrition: its importance during critical periods for cardiovascular and endocrine development.J Physiol. 1999; 514: 617-27Crossref PubMed Scopus (192) Google Scholar]. 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. In monozygotic 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 [4Ijzerman R.G. Stehouwer C.D. Boomsma D.I. Evidence for genetic factors explaining the birth weight–blood pressure relation: analysis in twins.Hypertension. 2000; 36: 1008-12Crossref PubMed Scopus (84) Google Scholar, 5Zhang J. Brenner R.A. Klebanoff M.A. Differences in birth weight and blood pressure at age 7 years among twins.Am J Epidemiol. 2001; 153: 779-82Crossref PubMed Scopus (46) Google Scholar, 6Loos R.J. Fagard R. Beunen G. Derom C. Vlietinck R. Birth weight and blood pressure in young adults: a prospective twin study.Circulation. 2001; 104: 1633-8Crossref PubMed Scopus (70) Google Scholar]. 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 [7Poulsen P. Vaag A.A. Kyvik K.O. Moller J.D. Beck‐Nielsen H. Low birth weight is associated with NIDDM in discordant monozygotic and dizygotic twin pairs.Diabetologia. 1997; 40: 439-46Crossref PubMed Scopus (275) Google Scholar, 8Poulsen P. Levin K. Beck‐Nielsen H. Vaag A. Age‐dependent impact of zygosity and birth weight on insulin secretion and insulin action in twins.Diabetologia. 2002; 45: 1649-57Crossref PubMed Scopus (72) Google Scholar, 9Bo S. Cavallo‐Perin P. Scaglione L. Ciccone G. Pagano G. Low birthweight and metabolic abnormalities in twins with increased susceptibility to type 2 diabetes mellitus.Diabet Med. 2000; 17: 365-70Crossref PubMed Scopus (92) Google Scholar]. 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 of fibrinogen in later life [10Barker D.J. Meade T.W. Fall C.H. Lee A. Osmond C. Phipps K. Stirling Y. Relation of fetal and infant growth to plasma fibrinogen and factor VII concentrations in adult life.BMJ. 1992; 304: 148-52Crossref PubMed Scopus (202) Google Scholar, 11Martyn C.N. Meade T.W. Stirling Y. Barker D.J. Plasma concentrations of fibrinogen and factor VII in adult life and their relation to intra‐uterine growth.Br J Haematol. 1995; 89: 142-6Crossref PubMed Scopus (93) Google Scholar]. An attempt to investigate the origins of this association is published in this issue of the journal. Tuya et al. [12Tuya C. Mutch W.J. Broom I. McNeill G. The effect of birth weight on clottable and intact fibrinogen levels: a twin study.J Thromb Haemost. 2005; 3: 1143-8Abstract Full Text Full Text PDF Scopus (7) Google Scholar] have investigated the association between birth weight and fibrinogen within twin pairs. In the within‐pair analysis in twins, there was a significant inverse association between differences in birth weight and clottable fibrinogen levels in dizygotic twin pairs [−0.34 g L−1 kg−1 (95% CI: −0.65, −0.02), P = 0.04], but not in monozygotic twin pairs [−0.12 g L−1 kg−1 (95% CI: −0.53, 0.28), P = 0.54]. This difference between dizygotic and monozygotic twins may not be statistically significant, but is in accordance with a previous study in twins. The findings are compatible with the hypothesis that genetic factors play an important role in the association between birth weight and fibrinogen. Because twin studies have shown that the association between birth weight and glucose metabolism is independent of genetic factors, the disappointing results of the search for genes related to both birth weight and diabetes are not surprising [13Rasmussen S.K. Urhammer S.A. Hansen T. Almind K. Moller A.M. Borch‐Johnsen K. Pedersen O. Variability of the insulin receptor substrate‐1, hepatocyte nuclear factor‐1alpha (HNF‐1alpha), HNF‐4alpha, and HNF‐6 genes and size at birth in a population‐based sample of young Danish subjects.J Clin Endocrinol Metab. 2000; 85: 2951-3PubMed Google Scholar, 14Lindsay R.S. Prochazka M. Baier L.J. Knowler W.C. Bogardus C. Hanson R.L. Currently identified genes affecting insulin resistance are not associated with birth weight in the Pima population.Diabet Med. 2002; 19: 882-4Crossref Scopus (5) Google Scholar, 15Frayling T.M. Hattersley A.T. McCarthy A. Holly J. Mitchell S.M. Gloyn A.L. Owen K. Davies D. Smith G.D. Ben‐Shlomo Y. A putative functional polymorphism in the IGF‐I gene: association studies with type 2 diabetes, adult height, glucose tolerance, and fetal growth in U.K. populations.Diabetes. 2002; 51: 2313-6Crossref PubMed Scopus (122) Google Scholar]. Although the mechanisms may not be obvious, further studies should investigate whether genotypes related to hypertension and fibrinogen are related to low birth weight, as the association of birth weight with blood pressure and fibrinogen may be influenced by genetic factors.