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The Epigenetic Basis of Twin Discordance in Age-Related Diseases

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The Epigenetic Basis of Twin Discordance in Age-Related Diseases 0031-3998/07/6105-0038R PEDIATRIC RESEARCH Vol. 61, No. 5, Pt 2, 2007 Copyright © 2007 International Pediatric Research Foundation, Inc. Printed in U.S.A. The Epigenetic Basis of Twin Discordance in Age-Related Diseases PERNILLE POULSEN, MANEL ESTELLER, ALLAN VAAG, AND MARIO F. FRAGA Steno Diabetes Center [P.P., A.V.], 2820 Gentofte, Denmark; Epigenetics Laboratory [M.E., M.F.F.], Spanish National Cancer Centre (CNIO), 28029 Madrid, Spain ABSTRACT: Monozygotic twins share the same genotype because have reported significantly lower concordance rates, which is they are derived from the same zygote. However, monozygotic twin considered evidence of a genetic component in the etiology of siblings frequently present many phenotypic differences, such as their Type 2 diabetes. Despite the indication that there is some susceptibility to disease and a wide range of anthropomorphic fea- genetic control, no fully penetrant genes have been identified tures. Recent studies suggest that phenotypic discordance between that in itself fully explains the common form of type 2 diabetes. monozygotic twins is at least to some extent due to epigenetic factors However, some studies have demonstrated associations between that change over the lifetime of a multicellular organism. It has been proposed that epigenetic drift during development can be stochastic various metabolic defects underlying the development of type 2 or determined by environmental factors. In reality, a combination of diabetes and polymorphisms in several susceptibility genes, such the two causes prevails in most cases. Acute environmental factors as PPAR␥ (6), PGC-1 (7), and, most recently, TCF7L2 (8). A are directly associated with epigenetic-dependent disease pheno- fully penetrant dominant disorder would result in 100% and 50% types, as demonstrated by the increased CpG-island promoter hyper- concordance in MZ and DZ twins, respectively (9). Incomplete methylation of tumor suppressor genes in the normal oral mucosa of concordance (Ͻ100%) between MZ twins, even in studies of smokers. Since monozygotic twins are genetically identical they are highly selected subjects, indicates the additional influence of considered ideal experimental models for studying the role of envi- environmental factors. Accordingly, in our study, half of the ronmental factors as determinants of complex diseases and pheno- affected MZ twin pairs were discordant for type 2 diabetes, types. (Pediatr Res 61: 38R–42R, 2007) providing further evidence that the DNA sequence alone cannot explain susceptibility to the disease (1). MZ TWINS IN THE STUDY OF AGE-RELATED NON-MENDELIAN DISEASES ENVIRONMENTAL FACTORS UNDERLYING TWIN DISCORDANCE Twin studies have been used extensively in medical re- search and are instrumental in estimating the relative impor- The cause of phenotypic discordance in MZ twins has tance of genetic versus nongenetic components in the etiology traditionally been attributed to postnatal environmental factors of human disease. The rationale underlying classical twin unique to the individual siblings of the pair (i.e. nonshared studies is the assumption that MZ twins are genetically iden- environment). Nevertheless, there is increasing evidence that tical, whereas DZ twins on average share 50% of their segre- MZ co-twins may differ due to postzygotic genetic, epigenetic, gating genes, and are as genetically different or similar as are and prenatal environmental factors, hence challenging the ordinary siblings. Similarity in MZ and DZ twin pairs can be assumption of genetic or epigenetic similarity that underlies established by means of concordance rates (for dichotomous the classical twin model. Genetic differences between MZ variables) and interclass correlation coefficients (for continu- co-twins arising from point mutations and chromosomal ab- ous variables). Phenotypes exhibiting a greater degree of normalities are rare and have only been seldom reported. similarity in MZ than in DZ twin pairs (i.e. greater concor- Epigenetic differences include skewed X-chromosome inacti- dance or interclass correlation coefficients) are traditionally vation in female twin pairs and loss of imprinting (10–12). considered to have a genetic etiological component. More recently, research has revealed different epigenetic mod- Common age-related complex non-Mendelian diseases ifications in autosomal genes in MZ twins (13–15). Our recent such as type 2 diabetes (1), Alzheimer’s disease (2), and investigation of global and locus-specific differences in DNA various cancers, including that of the breast (3) and prostate methylation and histone acetylation in young and elderly MZ (4), are all significantly heritable. For example, we, and others, twins showed that young MZ twin pairs are essentially indis- have previously reported concordance rates of type 2 diabetes tinguishable in their epigenetic markings, whereas elderly MZ of 50–92% among MZ twins (1,5). Most studies of DZ twins twin pairs have substantial variations in several tissues (16). The degree of discordance in epigenetic pattern was related to Received November 1, 2006; accepted November 11, 2006. environmental differences (i.e. arising from lifestyle and time Correspondence: Mario F. Fraga, Ph.D., Epigenetics Laboratory, Spanish National spent together) between twins. Moreover, differences in gene Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain; E-mail: [email protected] DOI: 10.1203/pdr.0b013e31803c7b98 Abbreviations: DZ, dizygotic; MZ, monozygotic 38R EPIGENETICS IN AGE-RELATED DISEASES 39R expression in the elder twin pairs were four times greater than sequence, and, unlike the static DNA sequence, display consid- those observed in the younger twin pairs (16). These findings erably plasticity. are of major importance for understanding the results of There is increasing evidence of epigenetic modulation oc- classical twin heritability and concordance analyses and high- curring early in life in response to environmental factors (26). light a potential mechanism by which environmental factors Studies of intrauterine-growth-retarded rats have demon- can regulate gene expression. Although the study design could strated that an adverse intrauterine environment is associated not distinguish whether differences in epigenetic modifications with an epigenetically induced down-regulation of key genes within twin pairs are related to disease discordance, the notion regulating ␤-cell development, differentiation and function of age-accumulating epigenetic modifications offers an attrac- (27). In addition, an adverse uterine environment induced by tive explanation for disease discordance, difference in age of maternal dietary protein restriction (28) or uteroplacental in- onset, and severity of disease between pairs of twins. sufficiency (29) has demonstrated gene-specific changes in Numerous epidemiologic and metabolic studies of various methylation state and hence gene expression levels in the liver populations throughout the world have yielded compelling and kidney in the offspring. Interestingly, maternal behavior evidence for an association between an adverse fetal environ- can change the epigenomic state of a gene in the offspring. ment and the development of glucose intolerance and associ- Weaver et al. (30) demonstrated that increased pup-licking, ated defects of glucose metabolism in adulthood (17–19). It grooming, and arched-back nursing changed the epigenome at has been hypothesized that a common genotype may result in the glucocorticoid receptor gene in the hippocampus, resulting low birth weight as well as disease in later life (20), and in greater expression of the glucocorticoid receptor and an several studies investigating the impact of birth weight on improved response to stress in adult offspring. Furthermore, adult disease were unable to adjust for genetic factors. MZ these molecular and phenotypic changes were shown to be twins who are discordant for disease are an excellent example reversible upon central infusion of the histone deacetylase of how genetically identical individuals can exhibit differences inhibitor trichostatin A. Hence, epigenetic modifications are and represent a unique model for studying the contribution believed to occur during prenatal and postnatal life, either due and role of environmental factors in disease development. to stochastic events or external environmental factors, and Using this design, we have demonstrated significantly lower thus to be obvious candidate molecular mechanisms for phe- birth weights in twins with type 2 diabetes compared with notypic variation. It is not currently known whether epigenetic their nondiabetic, genetically identical co-twins. Accordingly, modifications may regulate gene expression in humans who we have verified that the influence of birth weight is indepen- have been exposed to an adverse environment, whether such dent of genotype and other confounding variables, such as changes may be present throughout the entire life span or gestational age, maternal age, nutrition and height, sex, and whether prenatal operating factors may influence the rate of birth order in relation to other siblings (21). In addition, we the age related changes. have recently demonstrated a nongenetic association between birth weight and several pathophysiological mechanisms (e.g. MOLECULAR BASIS OF TWIN DISCORDANCE impaired insulin secretion and action) underlying the devel- opment of type 2 diabetes in elderly MZ twins (22,23). The interaction between environmental factors and pheno- The influence
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