Download What We Can Learn From Twins

Editorial
What We Can Learn From Twins
Congenital Heart Disease in the Danish Twin Registry
William T. Mahle, MD
O
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
ur understanding of the causes of congenital heart
defects has benefited tremendously from state-of-the-art
genetic and epigenetic tools. The rapid progress is due in part
to the development of novel, high-throughput, cost-effective
sequencing technology—so-called next-generation sequencing—that has made it possible to sequence the entire genome
or all genes (whole exome sequencing). However, to fully
understand the causes of congenital heart disease, it has been
important also to study population-based data that are available from large registries, which may take decades to establish. One such program has been in existence for >60 years
and has provided novel insights into the genetic and environmental mechanisms of many diseases including congenital
heart defects. The Danish Twin Registry is one of the oldest
twin registries in the world, and it contains information about
twins born in Denmark over the past 130 years.1
twinning might also contribute to the development of congenital heart disease.
To date, there have been discrepant findings regarding the
relationship of zygosity and the risk of developing congenital
heart disease among twins. Most studies have suggested that
birth defects are more common in monozygotic twins than
in dizygotic twins.6 Zygosity may not be easy to determine,
especially in large public health data sets. Some investigators
have sought to use like-sex as a proxy for zygosity.6 In general,
like-sex twins have been reported to have higher rates of birth
defects,7 although such associations have varied by the type
of birth defect. However, this sex-based approach has clear
limitations. One of the strengths of the Danish Twin study has
been the consistent use of a questionnaire to assign zygosity.
In comparison with cytogenetic testing, this questionnaire has
been shown to be highly reliable.8
Unlike several other studies, the present analysis did not
demonstrate a higher risk of congenital heart disease among
monozygotic twins in comparison with dizygotic twins. This
finding has important implications for understanding why
twin gestation may be associated with birth defects including congenital heart disease. The findings of the present study
would suggest that the intrauterine environment of twin gestation must somehow predispose to the development of congenital heart disease. It has been hypothesized that twin gestation
alters maternal nutrition to the fetus. Nutritional depletion is
more common in multiple gestation.9 Nutrient and micronutrient intake during pregnancy has been linked to fetal congenital heart defects.10 This may impact not only fetal growth,
but potentially organogenesis as well. It is possible that such
nutritional deficiency would make the fetus more susceptible
to other teratogenic factors such as prenatal exposures or poor
maternal health.
One controversial topic related to twin gestation relates
to assisted reproductive technology (ART). There has been
increased attention focused on the possible impact of ART on
the development of birth defects.11 The present study did not
include detailed data regarding ART. As such, it is possible
that the increased incidence of congenital heart disease among
dizygotic twins might simply reflect an increased use of ART,
because ART is known to result in a higher rate of multiplegestation births. This does not seem to be a likely explanation,
however, for several reasons. First, the increased risk of congenital heart disease for twin gestation was evident for several decades before the routine use of ART. In addition, recent
studies have suggested that ART does not appear to increase
the risk of birth defects in twin gestation, even though it may
increase the risk in singleton gestation.12
Great care has been given to the construction of the Danish
Twin Registry and the Danish National Patient Registry;
Article see p 1182
In the current study, Herskind et al2 analyze data from the
Danish Twin study, and the Danish National Patient Registry,
as well, to examine the relationship of twin gestation to the
development of congenital heart defects. Numerous investigators have suggested that twin gestation is associated with
an increased risk of birth defects, including congenital heart
disease.3–5 In a large study of a California birth defects surveillance program, Hardin and colleagues6 reported that the
risk of congenital heart disease was significantly increased
among twins for a variety of lesions. Lesions of the outflow
tract had the strongest association with twin gestation. The
present study confirms this association, demonstrating rather
convincingly that twin gestation carries an increased risk for
most forms of congenital heart disease.
Twin studies have been particularly valuable in understanding the impact of genetic and environmental factors
in the development of birth defects. When birth defects
are more common among monozygotic twins than dizygotic twins, one would assume that vascular factors including the twin-twin transfusion syndrome play a critical role
in teratogenesis. Alternatively, one might consider that the
genetic factors that contribute to the process of monozygotic
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Emory University School of Medicine, Atlanta, GA.
Correspondence to William T. Mahle, MD, Children’s Healthcare of
Atlanta, Emory University School of Medicine, 1405 Clifton Rd, NE,
Atlanta, GA 30322-1062. E-mail [email protected]
(Circulation. 2013;128:1173-1174.)
© 2013 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.113.005109
1173
1174 Circulation September 10, 2013
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
nonetheless, it must be recognized that the Danish National
Patient Registry identifies congenital heart lesions based on
International Classification of Diseases codes. Whereas the
overall accuracy for identifying congenital heart disease is
high, the positive predictive value for certain lesions, such
as truncus arteriosus and double outlet right ventricle, in this
registry is lower.13 The extent of phenotyping is an important
confounder in any genetic epidemiology study, and this is particularly the case in disorders, such as congenital heart disease, where there is substantial pleiotropy.
Population-based studies will continue to provide novel
insights into the etiology of congenital heart disease.
Particularly valuable will be the methodologic cross-linking
of such population-based studies as Herskind and colleagues
have done. One can imagine future projects that directly
link extensive registries such as the Danish Twin Study with
emerging epigenetic assays to advance our understanding of
congenital heart disease and possibly to design approaches to
prevent such birth defects in the coming decades.
Disclosures
None.
References
1.Skytthe A, Kyvik KO, Holm NV, Christensen K. The Danish Twin
Registry. Scand J Public Health. 2011;39(7 suppl):75–78.
2. Herskind AM, Pederson DA, Christensen K. Increased prevalence of congenital heart defects in monozygotic and dizygotic twins. Circulation.
2013;128:1182–1188.
3. Källén B. Congenital malformations in twins: a population study. Acta
Genet Med Gemellol (Roma). 1986;35:167–178.
4. Luke B, Keith LG. Monozygotic twinning as a congenital defect and
congenital defects in monozygotic twins. Fetal Diagn Ther. 1990;5:
61–69.
5. Li SJ, Ford N, Meister K, Bodurtha J. Increased risk of birth defects
among children from multiple births. Birth Defects Res A Clin Mol
Teratol. 2003;67:879–885.
6. Hardin J, Carmichael SL, Selvin S, Lammer EJ, Shaw GM. Increased
prevalence of cardiovascular defects among 56,709 California twin pairs.
Am J Med. Genet A. 2009;149A:877–886.
7. Ramos-Arroyo MA. Birth defects in twins: study in a Spanish population.
Acta Genet Med Gemellol (Roma). 1991;40:337–344.
8. Kyvik KO, Green A, Beck-Nielsen H. The most recent part of the Danish
Twin Registry. Establishment and analysis of zygote specific twinning
rates [in Danish]. Ugeskr Laeger. 1996;158:3456–3460.
9.
Luke B. Nutrition and multiple gestation. Semin Perinatol.
2005;29:349–354.
10. Shaw GM, Carmichael SL, Yang W, Lammer EJ. Periconceptional nutrient intakes and risks of conotruncal heart defects. Birth Defects Res A Clin
Mol Teratol. 2010;88:144–151.
11.Kuwata T, Matsubara S, Ohkuchi A, Watanabe T, Izumi A, Honma Y,
Yada Y, Shibahara H, Suzuki M. The risk of birth defects in dichorionic
twins conceived by assisted reproductive technology. Twin Res. 2004;7:
223–227.
12. Reefhuis J, Honein MA, Schieve LA, Correa A, Hobbs CA, Rasmussen
SA; National Birth Defects Prevention Study. Assisted reproductive
technology and major structural birth defects in the United States. Hum
Reprod. 2009;24:360–366.
13.Agergaard P, Hebert A, Bjerre J, Sørensen KM, Olesen C, Ostergaard
JR. Children diagnosed with congenital cardiac malformations at the
national university departments of pediatric cardiology: positive predictive values of data in the Danish National Patient Registry. Clin Epidemiol.
2011;3:61–66.
Key words: Editorials ◼ epidemiology ◼ valvular heart disease, congenital
What We Can Learn From Twins: Congenital Heart Disease in the Danish Twin Registry
William T. Mahle
Circulation. 2013;128:1173-1174; originally published online August 8, 2013;
doi: 10.1161/CIRCULATIONAHA.113.005109
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/128/11/1173
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation is online at:
http://circ.ahajournals.org//subscriptions/