Brief Reports
Sex-Related Clustering of Intracranial
Aneurysms Within Families
Laura C. Sijtsma, BSc; Gabriel J.E. Rinkel, MD; Ynte M. Ruigrok, MD
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Background and Purpose—Family history is important risk factor for intracranial aneurysms (ICA), but the pattern of
inheritance is unsettled. If ICA within families would cluster according to sex, this may have implications for risk
prediction and screening advice within families. We assessed the relationship between the sex of probands and their
affected first-degree relatives (FDRs) within families with ICA.
Methods—We used data from our prospectively collected database of families with known familial ICA. We calculated
relative risks for a female affected proband having a female affected FDR as compared with a male affected proband
having female affected FDR with corresponding 95% confidence intervals.
Results—We included 148 families with 376 affected FDR. For a female proband the relative risk for having a female
affected FDR compared with a male proband having an affected female FDR was 1.2 (95% confidence interval, 1.0–1.6).
Conclusions—The clustering of ICA within families is greater in women than in men, with an excess of affected female FDR in
female probands. However, because this excess is modest, our findings indicate that sex is not a relevant factor in risk prediction
or screening advice in families with ICA. (Stroke. 2015;46:1107-1109. DOI: 10.1161/STROKEAHA.115.008798.)
Key Words: intracranial aneurysm ◼ subarachnoid hemorrhage
A
Data Collection
positive family history is an important risk factor for
aneurysmal subarachnoid hemorrhage (aSAH) and intracranial aneurysms (ICA), with familial clustering occurring
in ≈10% of patients with aSAH.1 Serial screening for ICA is
recommended for individuals with 2 affected first-degree relatives (FDRs).2 Sex is another risk factor with a higher prevalence of ICA and higher incidence of aSAH in women than in
men.3,4 Whether the clustering of ICA within families occurs
according to sex is unknown. Such sex-related clustering may
have implications for risk prediction and screening advice
within families. Therefore, we determined the relationship
between the sex of affected probands and the sex of affected
FDR within families with ICA.
We constructed pedigrees and determined the affected proband and
the affected FDR of the proband for each family. The affected proband was defined as the first family member diagnosed with aSAH or
unruptured ICA based on family history. Affected FDRs of the families were stratified according to sex of the proband and were grouped
according to their relation to proband.
Data Analysis
To assess the relationship of the sex of affected probands and the sex
of affected FDR within families, we calculated relative risks (RRs)
with corresponding 95% confidence intervals for a female affected proband having a female affected FDR as compared with a male affected
proband having female affected FDR. In addition, we calculated RR
and 95% confidence interval for the subset of probands and FDR with
aSAH, thus excluding those probands and FDR with unruptured ICA.
By that we assessed whether larger clustering of aSAH and ICA within
families in women as compared with men might have been influenced
by a larger proportion of women undergoing screening as compared
with men. Both analyses were performed for all affected FDR together
but also by subdividing the affected FDR according to their type of
family relation to the proband, being parents, siblings, or children.
Methods
Study Population
From the prospectively collected database of a consecutive series
of families with familial ICA at the Department of Neurology and
Neurosurgery of the University Medical Center Utrecht, we used
all available information from April 1993 up to January 2014. A
positive family history was defined as ≥2 affected FDR (parents,
siblings, and children) with definite or probable aSAH5 or unruptured ICA. The episodes of aSAH were defined on the basis
of history and if available on medical records that were retrieved
from our or other hospitals. Unruptured ICA had to be diagnosed
by computed tomography, MR, or conventional angiography.
Patients with autosomal-dominant polycystic kidney disease were
excluded (n=4).
Results
We included 148 families with a total of 376 FDR of whom
148 were designated as affected probands and the remaining
228 family members as affected FDR. Of the 148 probands,
107 were women (72.3%) and 142 had an episode of aSAH
and 6 unruptured ICA. Of the 228 affected FDR, 153 were
women (67.1%), 148 had aSAH, and 80 unruptured ICA.
Received January 15, 2015; final revision received January 15, 2015; accepted January 27, 2015.
From the Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Correspondence to Ynte M. Ruigrok, MD, Department of Neurology and Neurosurgery, University Medical Center Utrecht, PO Box 85500, 3508 GA
Utrecht, The Netherlands. E-mail [email protected]
© 2015 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.115.008798
1107
1108 Stroke April 2015
Table 1. Relationship Between the Sex of Affected Probands
and the Sex of Affected First-Degree Relatives Within Families
With Intracranial Aneurysm
Proband
Female (n=172)
Male (n=56)
RR (95% CI)
Relative
Parents (n=18)
Mother
14/16 (88%)
2/2 (100%)
Not estimable
Siblings (n=127)
Sister
66/95 (69%)
17/32 (53%)
1.3 (0.9–2.0)
41/61 (67%)
13/22 (59%)
1.1 (0.8–1.9)
121/172 (70%)
32/56 (57%)
1.2 (1.0–1.6)
Children (n=83)
Daughter
All (n=228)
Women
CI indicates confidence interval; and RR, relative risk.
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For a female proband the RR for having a female affected
FDR as compared with a male proband having a female
affected FDR was 1.2 (95% confidence interval, 1.0–1.6;
Table 1). When including only probands and FDR who had
aSAH the RR is comparable: RR 1.2 (95% confidence interval, 1.0–1.8; Table 2). The RRs of the analyses subdividing the
affected FDR according to their type of family relation to the
proband were also comparable although no longer statistically
significant (Tables 1 and 2).
Discussion
Our results show a sex-related clustering within families with
ICA with affected female probands having a higher risk of
having female affected FDR as compared with male probands
having female affected FDR.
We found 1 previous Finnish study showing no effect of
sex on the transmission but also no preponderance of female
patients within the 126 families analyzed.6 As in other populations such a preponderance of female patients within families
exists7 this may explain that no effect of sex on the transmission was found in the Finnish.6
Table 2. Relationship Between the Sex of Affected Probands
and the Sex of First-Degree Relatives With Aneurysmal
Subarachnoid Hemorrhage Within Families With Intracranial
Aneurysm
Proband
Female (n=107)
Male (n=41)
RR (95% CI)
Relative
Parents (n=15)
Mother
12/13 (92%)
2/2 (100%)
Not estimable
Siblings (n=75)
Sister
37/52 (71%)
13/23 (57%)
1.3 (0.9–2.0)
41/61 (67%)
13/22 (59%)
1.3 (0.9–2.4)
80/107 (75%)
24/41 (59%)
1.3 (1.0–1.8)
Children (n=83)
Daughter
All (n=173)
Women
CI indicates confidence interval; and RR, relative risk.
Our observed sex-related clustering within families with
ICA may be influenced by female hormone levels,8 alone or
by interaction with genetic risk factors.9 Because hypertension is a risk factor for both sporadic and familial aSAH10 and
heritability for hypertension through the female line has been
described,11 hypertension might also contribute to the sexrelated clustering. We are not able to study the contribution of
hypertension to the observed sex-related interactions because
we have no systematically collected information on hypertension in our probands and FDR.
The strength of this study was the large number of families
analyzed all included from a single center. Our study also has
limitations that need to be addressed. First, details on family history may be inaccurate because part of the information
about family history was obtained from patients or relatives
and the accuracy of self-reporting of a familial history of
aSAH is not optimal.5 However, the potential imprecision in
reporting family history is unlikely to be related to the sex of
the proband. Second, women may be more likely to undergo
screening than men, which could potentially have led to an
over-representation of women with unruptured ICA identified
at screening. However, we excluded that such an over-representation of women influenced our findings, because we found
comparable results by only including probands and FDR with
aSAH and thus excluding those with unruptured ICA.
Although we found clustering of aSAH and unruptured ICA
within families according to female sex, the effect is small from
a clinical standpoint of view. Thus, sex is not a relevant factor in risk prediction or screening advice in families with ICA.
Further studies on the interaction between environmental risk
factors such as smoking and hypertension and female hormones
with genetic determinants of ICA may reveal more insight into
why aSAH and ICA cluster according to female sex.
Sources of Funding
Dr Ruigrok was supported by the Netherlands Organisation
for Scientific Research (NWO)-Veni-grant by the Netherlands
Organisation for Scientific Research (project no. 91610016).
Disclosures
None.
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Sex-Related Clustering of Intracranial Aneurysms Within Families
Laura C. Sijtsma, Gabriel J.E. Rinkel and Ynte M. Ruigrok
Downloaded from http://stroke.ahajournals.org/ by guest on June 18, 2017
Stroke. 2015;46:1107-1109; originally published online February 17, 2015;
doi: 10.1161/STROKEAHA.115.008798
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