221
A Study of Twins and Stroke
Lawrence M. Brass, MD; Jonathan L. Isaacsohn, MD;
Kathleen R. Merikangas, PhD; and C. Dennis Robinette, PhD
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Background and Purpose: Although there are strong genetic contributions to coronary artery
disease, only a few studies have considered heritable influences on stroke.
Methods: We investigated the role of genetic factors in stroke using the Twin Registry
maintained by the National Academy of Sciences-National Research Council. The registry
includes 15,948 male twin pairs born between 1917 and 1927. In 1985, 9,475 twins responded to
a mailed questionnaire, which covered vascular risk factors, cardiac events, and stroke.
Results: Analysis of twin pairs in which both responded to the questionnaire, and a question
on stroke, indicated proband concordance rates of 17.7% for monozygotic pairs and 3.6% for
dizygotic pairs (relative risk=4.3; ^ 2 =4.94, df=l;p<0.05).
Conclusions: This nearly fivefold increase in the prevalence of stroke among the monozygotic
compared with the dizygotic twin pairs suggests that genetic factors are involved in the etiology
of stroke. The twin study paradigm holds considerable promise for identifying both genetic and
environmental influences on stroke. (Stroke 1992;23:221-223)
G
enetic factors play a significant role in myocardial infarction and vascular risk factors.1
Aside from reported associations in small
numbers of cases with Mendelian diseases,2 few
studies have investigated the role of genetics in
stroke. Most have been circumstantial, and the results conflicting.3
Twin studies, comparing concordance rates between monozygotic and dizygotic twins, have long
been used to estimate the heritability of a trait or
disorder.14 These studies have been useful in understanding the heritability of complex traits such as
cardiovascular risk factors,56 diabetes,7 hypertension,8 lipid (cholesterol and lipoprotein) disorders,89
obesity,10 personality traits,11 cognitive functions,12
and cardiac mortality.1314 Results from these studies
have paved the way for the current investigations into
the molecular biology of cardiovascular disease. Twin
registries continue to provide important information
on the role of genetics in cardiovascular disease. As
From the Departments of Neurology (L.M.B.), Medicine
(J.L.I.), and Epidemiology and Public Health (K.R.M.), Yale
University School of Medicine, New Haven, Conn., and the
Medical Follow-up Agency (C.D.R.), National Research CouncilNational Academy of Sciences, Washington, D.C.
Supported in part by the Bristol-Myers Squibb Pharmaceutical
Research Institute and gifts to the Yale Stroke Program.
Presented in part at the 115th Annual Meeting of the American
Neurological Association, Atlanta, Ga., October 1990.
Address for correspondence: Lawrence M. Brass, MD, Yale
Stroke Program, Department of Neurology, LCI-700, Yale University School of Medicine, 333 Cedar Street, New Haven, CT
06510.
Received February 22, 1991; accepted September 30, 1991.
part of a preliminary investigation, we applied this
technique to the study of cerebrovascular disease.
Subjects and Methods
The sample for this study was the National Academy of Science-National Research Council Twin
Registry, a unique national resource. The details of
the construction of this twin panel have been described.15 In brief, birth certificates from the years
1917-1927, for multiple white male births occurring
in the continental United States, were reviewed.
Approximately 108,000 birth certificates were identified. It is estimated that this represents about 93% of
all such births occurring during these years.16 These
records were crossed with the master index file of the
Veterans Affairs (VA). This yielded 15,948 pairs of
twins who both had served in the military, most
during World War II and a minority during the
Korean conflict. These 31,896 individuals constitute
the initial cohort. The methods of zygosity determination have been previously described and are estimated to be correct in approximately 95% of twin
pairs.13
The methods of ascertainment and follow-up for
the twin registry have also been described.16 Periodic
mortality reviews are performed through the computer-based Beneficiary Identification and Records Locator Subsystem of the VA. Veterans are eligible for
a burial allowance and the VA is notified of about
98% of deaths among World War II veterans by
relatives or morticians claiming this allowance.17 Survival for veterans is slightly better compared with the
US population of the same sex and age.18 Additional
222
Stroke Vol 23, No 2 February 1992
information on nonresponding living or deceased
siblings of affected individuals can be obtained by
cross-reference with the VA patient treatment file.
In the classic twin model, the difference between
the within-pair variances of dizygotic and monozygotic twins is a maximum likelihood estimate of the
genetic variation within dizygotic twins.19 There are
many available formulas for estimating concordance
and heritability in twin studies.2021 Because members
of the pairs were identified independently, concordance was estimated by calculating the probandwise
concordance rate.2223 In this method, the number of
affected individuals is divided by the number of index
cases. The significance was measured by x2 analysis.
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Results
Approximately 8,000 of the initial cohort are dead.
Of the 24,000 individuals still alive, there are approximately 9,500 twin pairs with both members alive.
There were 9,475 individuals who responded to the
1985 survey (4,292 monozygotic twins, 4,664 dizygotic
twins, and 519 twins of unknown zygosity). Of the
complete 2,722 twin pairs, there were 1,382 monozygotic twin pairs, 1,221 dizygotic twin pairs, and 119
twin pairs of unknown zygosity. To the question,
"Have you ever been told by a doctor that you had a
stroke?" members of the twin panel responded as
follows: 292 reported having been told of a stroke;
9,023 answered "No"; 24 were unsure; and 136 left
the question blank.
The prevalence of stroke in the entire cohort was
3.1% (292 of 9,315). It was the same for monozygotic
(3.1%, 131 of 4,220) and dizygotic (3.1%, 143 of
4,585) twins. (Note: "twin" refers to an individual,
and "twin pair" refers to a pair of twins; i.e., two twins
are in a twin pair.) The data are given in Table 1.
The probandwise concordance rate for the
monozygotic twins was 0.177 (14/[14+65]) and for
the dizygotic twins 0.036 (2/[2+53]). By \2 analysis
(comparing the number of individuals in concordant
pairs to the total number of pairs), * 2 =4.94 (df=l).
This corresponds to a relative risk of 4.3 (/><0.05).
Discussion
In the classic twin study, a comparison is made
between monozygotic and dizygotic twins. If genes
influence the prevalence of stroke, there should be a
greater concordance rate for stroke among monozygotic twin pairs than dizygotic pairs. Several assumptions are made in applying the twin method, including the degree of environmental similarity and
similarities between types of twins (dizygotic twins
tend to be more frequently associated with older
mothers, previous siblings, and fertility drugs; this is
not true for monozygotic twinning). These issues
have not had a significant impact on previous studies
of cardiac risk and, similarly, are not expected to
significantly influence our conclusions.24
Published work with twins and cerebrovascular
disease is limited to two reports. One study demonstrated a genetic influence of smoking on carotid
TABLE 1. Number of Twin Pairs and Individual Twins
Responding to 1985 Survey
Responses to
stroke question
Twin pairs
No/No
Yes/No
Yes/Yes
Individual twins
Blank
No
Yes
Unsure
Monozygotic
Pairs of Individual
twins
twins
1,271
65
7
39
Dizygotic
Pairs of
twins
Individual
twins
1,128
53
1
39
60
4,089
131
12
67
4,442
143
12
Table summarizes data from the question, "Have you ever been
told by a doctor that you had a stroke?" Top part of table refers to
twin pairs (e.g., column 1, line 2: in 65 monozygotic pairs of twins,
one twin answered yes and the other answered no). Lower part of
table refers to twins as individuals and gives responses of all twins
answering the survey, regardless of whether their brothers completed the questionnaire.
atherosclerosis25; Another study was unable to document a genetic effect on "cerebrovascular deaths,"
but suffered from small numbers and poor documentation of the cause of death.26-27
The difference between the concordance rates of
stroke of monozygotic and dizygotic twins in our
study suggests that there is a genetic contribution to
stroke prevalence in this cohort. There were too few
twin pairs with stroke to make a reliable estimation
of the magnitude of heritability.
Although this study concentrated on possible genetic influences of stroke prevalence, this is only part
of the possible genetic contributions to cerebrovascular disease. Animal studies suggest that genetic
factors may play a role in the susceptibility to infarction during cerebral ischemia.28 It also seems likely
that there are genetic influences on recovery after a
stroke.
Heritable risk does not imply unmodifiable risk.
The risk of cardiovascular disease associated with an
apparently inherited predisposition appears to be
profoundly affected by modifiable behavior. For example, in one study, over two thirds of the familial
risk of cardiovascular mortality was due solely to the
interaction of family history with smoking habit (i.e.,
susceptibility to cigarette smoking) and was therefore
potentially avoidable.29
Although biases may exist between respondents
and nonrespondents in any large survey, this has
been studied in a subgroup of our cohort. Minor
differences did exist: respondents were slightly more
obese and smoked less. The analyses used in this
study should be relatively unaffected by this selection.30 Other major potential biases of this study
design include the following: It is a survival cohort,
stroke is self-reported, and information on stroke
subtypes is not available. In spite of these limitations,
Brass et al A Study of Twins and Stroke
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this preliminary investigation should be encouraging
to those searching for a heritable role in stroke risk.
If a genetic risk is confirmed for stroke, early
preventive measures can begin in high-risk groups as
early as childhood, an approach already being applied to cardiovascular disease.3132 Demonstration of
a significant heritable risk for stroke should also
prompt, and help direct, further investigation into
the molecular mechanisms of the genetic influences
on stroke and may identify new approaches for stroke
prevention and treatment, as it has for cardiovascular
research.33
As the members of this registry continue to age,
their stroke risk increases dramatically. We plan to
use our data to prepare for a larger, prospective
investigation, before deaths in this aging population
make it impossible. Our next study should provide
estimates of heritability, including the heritable contribution to individual stroke risk factors and the
impact of the genetic determination of vascular risk
factors on the genetic determination of stroke.
Acknowledgments
The authors wish to thank Walter N. Kernan, MD,
for his critical review and helpful suggestions (including those we could not include in this manuscript).
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KEY WORDS • cerebrovascular disorders • genetics • twins
A study of twins and stroke.
L M Brass, J L Isaacsohn, K R Merikangas and C D Robinette
Stroke. 1992;23:221-223
doi: 10.1161/01.STR.23.2.221
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