Genetic Predisposition to Stroke in
Relatives of Hypertensives
M. Nicolaou, BA; A.L. DeStefano, PhD; I. Gavras, MD; L.A. Cupples, PhD; A.J. Manolis, MD;
C.T. Baldwin, PhD; H. Gavras, MD; L.A. Farrer, PhD
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Background and Purpose—The genetic basis of stroke is poorly understood. We evaluated patterns of familial aggregation
of hypertension and stroke to test the hypothesis that inherited susceptibility to these disorders may be determined by
a common set of factors.
Methods—Genealogical and medical history information was obtained for a cohort of 354 hypertensive probands
ascertained in a clinic-based setting, their 1427 first-degree relatives, and 239 of their spouses. Risks of stroke and
hypertension in biological and nonbiological relatives were compared with the logistic model of the generalized
estimating equations adjusted for age and sex.
Results—The risk of hypertension was higher for the parents and siblings of the probands than for spouses (odds ratio
[OR]⫽2.4; 95% CI, 1.8 to 3.4; OR⫽2.2; 95% CI, 1.6 to 3.0, respectively). When the spouses were used as a reference
group, the risk of stroke for parents of the hypertensive probands was 7.3 times higher (OR⫽7.3; 95% CI, 3.6 to 14.8),
while a nonsignificant but slightly increased risk for siblings (OR⫽1.6; 95% CI, 0.8 to 3.3) was observed. Controlling
for hypertension, obesity, smoking, coronary heart disease, diabetes, and cholesterol resulted in decreased estimates of
the risk of stroke for parents and siblings (ORparents⫽5.4; 95% CI, 2.6 to 11.2; ORsiblings⫽1.2; 95% CI, 0.6 to 2.5). The
risk of stroke was significantly higher for hypertensive parents and siblings than for nonhypertensive parents (OR⫽5.2;
95% CI, 2.8 to 9.7) and siblings (OR⫽5.8; 95% CI, 2.1 to 15.9). A history of hypertension was not associated with an
increased risk for stroke in spouses (OR⫽0.7; 95% CI, 0.2 to 3.1). The risk of stroke in hypertensive relatives of
probands with stroke was higher than that of the normotensive relatives (OR⫽13.4). A less elevated risk ratio was
observed in the relatives of probands who did not have a stroke (OR⫽4.0).
Conclusions—Our data showing a higher occurrence of hypertension and stroke in parents of hypertensive probands
compared with spouses suggest that some of the genetic factors predisposing to these conditions may be the same. The
slightly increased risk to siblings compared with spouses was not significant, suggesting that elucidation of these factors
through family studies of stroke may be difficult because of secular trends toward improved treatment for hypertension.
Although a history of hypertension increases the risk of stroke among parents and siblings, multivariate analyses
revealed a familial component to stroke independent of hypertension. (Stroke. 2000;31:487-492.)
Key Words: genetics 䡲 hypertension 䡲 stroke outcome
D
Hypertension is the most influential known risk factor for
stroke, conferring an increased odds of 1.5 to 3.0 depending
on age, sex, and the severity of hypertension.1 Stroke incidence is directly proportional to age, with much higher rates
and poorer survival in people older than 65 years.2,3 Previous
studies have shown a higher risk for men than for women up
to age 65, while this sex-related difference was reversed for
those older than 65 years.1 Alter et al4 observed an association
between history of hypertension and recurrence of stroke. It is
well recognized that hypertension aggregates in families,
suggesting a genetic basis. In fact, genes have been identified
for several rare syndromic forms of hypertension.5,6 Family
espite the recent decline in the stroke mortality rates,
stroke is still the most common life-threatening neurological disease and the third leading cause of death in the
United States after heart disease and cancer.1,2 A large portion
of the population is disabled as a consequence of stroke.
Recent advances in the treatment of stroke and the underlying
causes plus the control of certain risk factors such as blood
pressure, salt intake, cigarette smoking, and weight can
account for the trends in mortality. Although the available
treatments for stroke have been helpful, the most effective
way to decrease the mortality and morbidity of stroke is
prevention, especially early in life.
Received June 3, 1999; final revision received November 22, 1999; accepted November 22, 1999.
From the Departments of Medicine (Genetics Program [M.N., A.L.D., L.A.F.] and Hypertension Section [I.G., A.J.M., H.G.]), Epidemiology and
Biostatistics (M.N., A.L.D., L.A.C., L.A.F.), and Neurology (A.L.D., L.A.F.), and the Center for Human Genetics (C.T.B.), Boston University School
of Medicine (Mass).
Correspondence to Lindsay A. Farrer, PhD, Genetics Program, L320, Boston University School of Medicine, 715 Albany St, Boston, MA 02118.
E-mail [email protected]
© 2000 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
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February 2000
history of stroke is perceived to be an important risk factor for
stroke, but the importance of this risk factor has not been
confirmed conclusively by epidemiological studies.7–17 To
further understand the genetic relationship between stroke
and hypertension, we evaluated the aggregation of stroke in
families prone to hypertension.
TABLE 1. General Information of All Subjects Included
in the Study
Male
Subjects and Methods
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Statistical Analysis
The logistic regression model of the generalized estimating equations
(GEE)18,19 approach was used to assess the familial pattern of stroke
and its relationship to hypertension. Hypertension and stroke were
alternately considered as outcome and predictor variables. All
regression models were adjusted for age and sex. Age was considered the age of onset for those who developed stroke or censoring
age (ie, current age or age of death) for all other individuals. Risk
ratios for disease and the corresponding 95% CIs were computed. A
subset of analyses also adjusted for the presence or absence of
obesity, coronary heart disease, diabetes, high cholesterol (⬎200
mg/dL), and history of smoking. Analyses included parents, siblings,
and spouses of the probands (the spouses were considered the
reference group). In studying the relationship of stroke and hypertension, the analyses were done separately for parents, siblings, and
spouses. Additional analyses were performed in which families were
stratified by stroke status of the proband. Furthermore, risk of stroke
was assessed in the families of the 204 white and 91 black probands
separately.
The risk of stroke for the first-degree relatives and spouses of the
hypertensive probands was estimated with survival analysis
techniques based on a maximum likelihood approach that accounts for missing censoring information.20 The risk of stroke
was estimated for hypertensives and normotensives. The log-rank
test was used to test the difference in risk among hypertensives
and normotensives.
Results
The study sample was composed of 354 hypertensive probands and their 630 parents, 797 siblings, and 239 spouses
(Table 1). Mean age was higher in female parents
(P⫽0.0007) and siblings (P⫽0.01), while in spouses men had
a higher mean age (P⫽0.0004). The frequencies of stroke
were the same in men and women in all groups of relatives.
Total
Probands
Total n
Hypertension (%)
Subjects were ascertained between January 1996 and December
1998 at outpatient units and collaborating clinics of the Boston
University Medical Center. The probands were chosen on the basis
of a diagnosis of hypertension (consistent systolic blood pressure
⬎140 mm Hg or diastolic blood pressure ⬎90 mm Hg confirmed on
consecutive measurements). Individuals taking long-term antihypertensive drugs were considered to be hypertensive even if their blood
pressure was within normal limits. Patients signed an informed
consent, which was approved by the Institutional Review Board at
Boston University Medical Center. Family history and medical
history information was collected with the use of standardized
questionnaire instruments administered by direct interview or completed by the patient at home. Additional family informants were
contacted to ensure accuracy and completeness of the responses.
Families were ascertained consecutively to minimize the potential
bias of selecting families with many individuals with hypertension.
The family history focused on first-degree relatives (ie, parents,
siblings, and children) and spouses. Children were excluded from
this study since the occurrence of stroke would be rare in this age
cohort. Occurrence, age of onset, and treatment of stroke were
determined on the basis of medical records or information given by
the proband or proxy informant. The diagnosis of stroke was based
on standard clinical criteria,1 ie, history, neurological examination,
plus, in recent years, brain imaging procedures. Data forms were
reviewed by at least 2 project personnel and computerized with the
use of an Oracle database.
Female
Stroke (%)
Age, mean⫾SD, y
164
190
354
164 (100)
190 (100)
354 (100)
10 (6.1)
16 (8.4)
26 (7.3)
60.5⫾12.8
63.2⫾12.8
61.9⫾12.8
Parents
Total n
Hypertension (%)
Stroke (%)
Age, mean⫾SD, y
311
319
119 (38.3)
196 (61.4)
630
315 (50)
49 (15.8)
68 (21.3)
117 (18.6)
69.0⫾14.1
73.6⫾14.7
71.4⫾14.6
378
419
797
205 (48.9)
379 (47.6)
Siblings
Total n
Hypertension (%)
Stroke (%)
Age, mean⫾SD, y
174 (46)
21 (5.6)
27 (6.4)
57.1⫾15.1
60.1⫾15.2
48 (6)
58.7⫾15.2
Spouses
Total n
Hypertension (%)
Stroke (%)
Age, mean⫾SD, y
119
120
239
39 (32.8)
39 (32.5)
78 (32.6)
5 (4.2)
4 (3.3)
9 (3.8)
64.9⫾11.7
58.8⫾13.1
61.7⫾12.8
The prevalence of stroke was at least 3 times greater among
parents than in probands (P⬍0.0001), siblings (P⬍0.001), or
spouses (P⬍0.001). Approximately one half of the parents
and siblings had hypertension, but fewer than one third of the
spouses were hypertensive.
The onset of stroke in parents (67.6 years) occurred earlier
than in siblings (73.5 years; P⫽0.006) and spouses (73.3
years; P⫽0.20). Hypertensive individuals had a 3-year earlier
onset age of stroke than nonhypertensive individuals, but this
difference was not significant.
The logistic regression model of the GEE was used to
compare the age- and sex-adjusted odds of hypertension or
stroke in the parents and siblings with the corresponding odds
in spouses. Table 2 shows that parents and siblings had an
approximately 2.5 times higher risk of being hypertensive
compared with spouses (P⫽0.0001). Adjustment for other
factors did not change the estimates. Parents had a much
higher risk of stroke than spouses, whereas the slightly
increased risk of stroke among siblings compared with
spouses was not significant. Because these families were
ascertained through hypertensive probands, the possibility of
increased familial incidence of stroke due to factors underlying hypertension was explored by adjustment for hypertension in the regression model that considered stroke as the
outcome. Adjustment for hypertension as well as for several
other covariates decreased (but not significantly) the risk of
stroke in parents compared with spouses.
To explore the possibility that the higher risk seen in
parents but not in siblings was due to an age cohort effect
since parents are on average 10 years older than the siblings
Nicolaou et al
TABLE 2.
Familial Aggregation of Hypertension and Stroke
Outcome
TABLE 3.
OR (95% CI)
P
Parents
2.4 (1.8–3.4)
0.0001
Siblings
2.2 (1.6–3.0)
0.0001
Spouses
Referent
Relationship
Genetic Component of Stroke and Hypertension
Hypertension (n⫽1289)
Hypertension* (n⫽1250)
Parents
2.8 (1.9–4.1)
0.0001
Siblings
2.4 (1.7–3.3)
0.0001
Spouses
Referent
Parents
7.3 (3.6–14.8)
0.0001
Siblings
1.6 (0.8–3.3)
0.22
Spouses
Referent
Parents
5.4 (2.6–11.2)
0.0001
Siblings
1.2 (0.6–2.5)
0.68
Spouses
Referent
Relationship of Stroke and Hypertension
Relation Hypertension Total n n (With Stroke)
Parents
489
OR (95% CI)
P
0.0001
Yes
267
92
5.2 (2.8–9.7)
No
172
14
1.0
Siblings
Yes
367
40
5.8 (2.1–15.9)
No
313
6
1.0
Spouses
Yes
77
3
0.7 (0.2–3.1)
No
130
6
1.0
0.0006
0.6626
Results are from GEE logistic model, adjusted for age and sex with stroke as
the outcome.
Stroke (n⫽1303)
Stroke† (n⫽1251)
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Results are from GEE Logistic Model, Adjusted for Age and Sex.
*Adjusted for obesity, smoking, coronary heart disease, diabetes, and
cholesterol level.
†Adjusted for hypertension, obesity, smoking, coronary heart disease,
diabetes, and cholesterol level.
and spouses (reflecting the fact that most parents have been
followed until death), analyses were repeated on samples
stratified on the basis of an age cutoff of 65 years. For the
group aged ⬍65 years, the parents (odds ratio [OR]⫽13.2;
95% CI, 4.6 to 38.5) but not the siblings (OR⫽1.9; 95% CI,
0.7 to 5.7) had a significantly higher risk than spouses. When
we adjusted for all covariates including hypertension, these
effects were decreased to 8.2 (95% CI, 2.7 to 25.2) and 1.3
(95% CI, 0.4 to 4.0) for the parents and siblings, respectively.
A similar trend was observed for the group aged ⱖ65 years,
in which the parents showed an increased risk of stroke
(OR⫽4.6; 95% CI, 1.8 to 12.0) compared with the spouses,
while the siblings showed a nonsignificant but increased odds
(OR⫽1.4; 95% CI, 0.5 to 3.8). These results were nominally
changed with the adjustment of all the covariates (OR⫽4.0;
95% CI, 1.5 to 10.7 for the parents and OR⫽1.2; 95% CI, 0.4
to 3.3 for the siblings).
To study the familial aggregation of hypertension and
stroke, risk of stroke was estimated for groups of parents,
siblings, and spouses stratified by hypertension status. The
pattern of risk for stroke differed between biological relatives
and spouses. The risk of stroke among the hypertensive
parents and siblings was increased ⬎5 times compared with
the respective nonhypertensive reference groups; however,
the risk of stroke was not increased among hypertensive
spouses compared with normotensive spouses (Table 3). In
Table 4, stratification of families by stroke status of the
proband suggested that the odds of stroke in hypertensive
relatives was substantially greater in families of probands
with stroke (OR⫽13.4) than in families of stroke-free probands (OR⫽4.0), but this difference was not significant
(P⫽0.33). The results presented in Table 4 remained unchanged after adjustment for all the covariates.
The relationship of stroke and hypertension was also
studied by estimating the cumulative risk of stroke for the
biological relatives and spouses of the probands stratified by
hypertension status (Figure ). The cumulative risk of stroke
for hypertensive first-degree relatives was consistently higher
than that for nonhypertensive first degree relatives after 50
years of age, and this difference was statistically significant
(log-rank test, P⫽0.0001). The risk of stroke at the maximum
onset age common to both groups (80 years) was significantly
higher in the hypertensives (25%) than in the normotensives
(7%). There was no difference in the lifetime risk of stroke
among hypertensive and normotensive spouses (log-rank test,
P⫽0.48).
The prevalence of hypertension is known to differ by
race.21 In our sample we studied the familial aggregation of
stroke and its relation to hypertension separately for whites
and blacks. The white subgroup was composed of 204
probands and their 366 parents, 476 siblings, and 140
spouses, while the black subgroup was composed of 91
probands and their 157 parents, 228 siblings, and 49 spouses.
The risk of stroke for hypertensive relatives versus that for
normotensive relatives was higher among blacks (ORparents⫽
9.9; 95% CI, 1.2 to 79.1; ORsiblings⫽15.23; 95% CI, 2.1 to
109.3) than among whites (ORparents⫽5.3; 95% CI, 2.5 to 11.1;
ORsiblings⫽3.9; 95% CI, 1.3 to 11.7). Parents of white hypertensive probands had a higher odds of stroke (but not
significantly) than parents of black hypertensive probands
(ORwhite⫽8.3; 95% CI, 3.3 to 21.0; ORblack⫽4.7; 95% CI, 1.1
to 21.2), while the ORs for the siblings were similar in the 2
ethnic groups.
Discussion
Evidence for a genetic basis of stroke is suggested by family
and twin studies. In the Framingham Offspring Study, it was
TABLE 4. Relationship of Stroke and Hypertension Stratified
on the Stroke Status of Proband
Stroke
Among
Probands
Yes
No
Hypertension
Total n
n (Stroke)
OR (95% CI)
P
Yes
58
13
13.4 (1.7–102.9)
0.0129
No
32
1
1.0
Yes
638
119
4.0 (2.6–6.3)
No
577
26
1.0
0.0001
Results are from GEE logistic model, adjusted for age and sex with stroke as
the outcome.
490
Stroke
February 2000
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Cumulative risk of stroke stratified by
hypertension status for first-degree relatives and spouses.
shown that a history of paternal (relative risk⫽2.4) or
maternal (relative risk⫽1.4) transient ischemic attack or
stroke was associated with the prevalence of transient ischemic attack and stroke in the offspring.7 This effect diminished
after adjustment for age, sex, and other confounding risk
factors. Graffagnino et al8 found that a larger percentage of
patients with stroke had a family history of stroke than did
age- and sex-matched control subjects. A recent Finnish study
observed that a positive parental history of stroke was a
predictor for the risk of stroke.10 Kubota et al,11 using a
univariate analysis, showed that family history of subarachnoid hemorrhage and intracerebral hematoma was associated
with an increased risk for each of these subtypes of stroke
(OR⫽11.24 and OR⫽2.39, respectively), while family history of cerebral infarction was not a significant risk factor for
developing stroke of this type. In a separate study, firstdegree relatives were found to have a risk almost 7 times
higher than second-degree relatives of developing subarach-
noid hemorrhage.9 However, family history and stroke risk
were unrelated in several other studies.12–14 Perhaps the most
compelling evidence for a genetic risk of stroke comes from
twin studies. Brass et al15 estimated a 17.7% concordance rate
for stroke among monozygotic twins, whereas the concordance rate for dizygotic twins was only 3.6%. Although these
relatively low concordance rates implicate a substantial environmental influence, the high rate in monozygotic twins
relative to dizygotic twins supports the hypothesis for a major
genetic contribution to the prevalence of stroke.
Our study demonstrated a higher risk of hypertension in
biological relatives of hypertensive probands compared
with spouses. Similarly, the higher risk of stroke in the
parents and siblings (ORparents⫽7.3, ORsiblings⫽1.6) compared with the spouses suggests that stroke also aggregates
in these families. Coaggregation of hypertension with
stroke could account for a large part for the increased
familial risk of stroke. The risk of stroke in the first-degree
Nicolaou et al
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relatives was decreased (ORparents⫽5.2, ORsiblings⫽1.2) once
the effect of hypertension on stroke was accounted for, but
the effect seen in the parents remained significantly higher
than that seen in the spouses. Previous studies suggest that
a variety of risk factors (obesity, smoking status, coronary
heart disease, diabetes, and high cholesterol level) inflate
the risk of stroke.1,22–25 However, adjustment for these risk
factors resulted in only a small decrease in the odds of
developing stroke for the first-degree relatives in our
modeling studies. Thus, most of the unexplained variance
in risk of stroke is likely due to unmeasured shared
environmental or genetic factors.
We observed a significantly increased risk of stroke for
parents but not for siblings. One explanation for this difference could be the variability in age distributions among
parents, siblings, and spouses. This explanation is unlikely
since the age-stratified analyses showed a similar effect
within age groups. A more likely explanation is a secular
trend resulting in better treatment or better prevention measures of the underlying causes of stroke for the generation
encompassing most of the siblings and spouses. If we assume
that susceptibility to stroke is governed by the interaction of
genetic and environmental factors, removing some nongenetic risk factors would decrease the risk of stroke. Thus, the
relatively recent introduction of better treatments and preventive measures for hypertension might give the appearance of
a reduced risk to siblings when, in fact, parents and siblings
have the same genetic predisposition to stroke.
Coaggregation of stroke and hypertension in biological
relatives of the probands was higher than expected given the
frequencies of the individual conditions. Hypertensive relatives had a ⬎5-fold increased risk of stroke than the normotensive relatives. In contrast, the risk of stroke was the same
in hypertensive and normotensive spouses. One possible
explanation for this is that since the spouses are close to the
probands who are hypertensive, they have better knowledge
of the environmental risk factors for hypertension and stroke
and are thus more likely to follow certain preventive measures (ie, better diet, exercise). Alternatively, individuals with
genetic susceptibility to hypertension (siblings and parents)
are more likely to develop stroke than hypertensive individuals without such susceptibility (ie, spouses). A higher risk of
stroke was observed for the normotensive spouses than for
the hypertensive spouses after the age of 75 years, suggesting
that factors other than hypertension may be involved in the
development of stroke. The relationship of stroke and hypertension was also observed when the risk of stroke was
examined in hypertensive and nonhypertensive relatives of
probands with stroke compared with relatives of probands
without stroke. The observation that hypertensive relatives of
probands with stroke had a 3-fold higher risk of stroke than
hypertensive relatives of probands without stroke suggests
that some of the genetic factors for stroke and hypertension
may be the same. Moreover, the results showing that the odds
of stroke among hypertensives versus normotensives in
blacks are higher than the corresponding odds in whites
suggest that the relationship between stroke and hypertension
varies across these ethnic groups.
Genetic Component of Stroke and Hypertension
491
Our study has several strengths. This is 1 of the 2 largest
family studies of stroke7 and, to our knowledge, the first
study that evaluated familial coaggregation of stroke and
hypertension. Second, our design exploits the fact that family
members tend to share certain environmental and cultural
factors, although the sharing among siblings occurs primarily
in early life, whereas comparisons involving spouses adjust
only for exposures in adulthood. Third, we used multiple and
rigorous analytical methods to account for several known risk
factors that obfuscate the effects of the genetic component to
stroke.
There are caveats to the interpretation of our results
associated with diagnostic uncertainty and study design. First,
the relatives of the probands were not examined in a manner
as rigorous as that for the probands, and thus there is the
possibility of misclassification. However, family history information was collected with the use of standardized procedures, including multiple informants to reduce the possibility
of misclassification due to recall bias, and this approach has
been shown to be highly reliable.26,27 Misclassification may
be more prominent in the prior generation (ie, parents), likely
resulting in the underdiagnosis of hypertension. Thus, this
bias would unlikely weaken the strong correlation between
stroke and hypertension in parents, ie, 87% of the parents
with stroke were known to be hypertensive. Second, our
study does not allow for the possibility of varying genetic risk
by stroke subtype. We did not stratify our subjects for several
reasons. Although stroke is a result of 2 pathological processes, ischemia (80%) and hemorrhage (20%), a number of
stroke types are included in each of these categories that
would be too small (in sample size) to show an effect. The
reliability of information regarding causes of stroke in relatives is compromised in the case of the parents who had
stroke at an age when diagnostic procedures were limited.
There is also no logical way to divide the subjects since there
can be multiple distinct causes of stroke within a family.
Finally, despite the fact that antihypertensive medications are
associated with reduced occurrence of stroke,28,29 we did not
account for treatment of subjects in this study. It is difficult to
obtain accurate medication history information on relatives.
Even when data are available, there are no standard methods
to make a meaningful adjustment given the complexity of the
multiple medications prescribed to an individual simultaneously or at different times. Although we did not adjust for
treatment, there is no reason to expect differences in treatment between our comparison groups (eg, siblings of patients
and spouses), except for differences due to age of the
subjects, which were explored above.
Our results suggest that biological relatives of hypertensive
probands have a greater risk of stroke than persons in the
general population, adjusted for age, sex, and hypertension.
This excess risk might be due to genetic factors, which
enhance susceptibility to both disorders. A portion of the
genetic component of stroke may be independent of hypertension, as suggested by a residual increased risk in parents
after controlling for hypertension. Coaggregation of hypertension and stroke in these relatives also suggests that genes
influencing susceptibility to hypertension may also be risk
factors for stroke. One such candidate is the angiotensin
492
Stroke
February 2000
1– converting enzyme gene, in which an insertion-deletion
polymorphism has been associated with hypertension30,31 and
stroke,32,33 although the role of angiotensin 1– converting
enzyme in hypertension is controversial.34,35 Alternatively, a
common genetic basis for stroke and hypertension might be
affected through genes underlying the risk factors for these
traits (eg, obesity, atherosclerosis, diabetes). Advancements
in prevention of stroke have made the task of finding genetic
factors for stroke difficult because many genetically vulnerable individuals avoid detection. Our data suggest that greater
emphasis should be placed on the evaluation of loci linked to
hypertension for an association with stroke.
Acknowledgments
This study was supported in part by Public Health Service grant P50
HL55001 and an award from the American Heart Association (to
M.N.). We would like to thank all the participants in this study.
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Genetic Predisposition to Stroke in Relatives of Hypertensives
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Gavras and L. A. Farrer
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Stroke. 2000;31:487-492
doi: 10.1161/01.STR.31.2.487
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