Elsevier

The Lancet Neurology

Volume 6, Issue 2, February 2007, Pages 125-133
The Lancet Neurology

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Heritability of ischaemic stroke in women compared with men: a genetic epidemiological study

https://doi.org/10.1016/S1474-4422(06)70683-4Get rights and content

Summary

Background

Ischaemic stroke is partly heritable. However, although the genetic and non-genetic factors responsible could be sex-specific, interactions between the sex of the parent affected and the sex of the proband or affected siblings are unknown. We sought to assess the relation between the sex and phenotype of affected probands and the sex of affected first-degree relatives.

Methods

We determined the prevalence of history of stroke in the mother, father, and other first-degree relatives in female and male probands with ischaemic stroke or transient ischaemic attack in the population-based Oxford Vascular Study (OXVASC). We validated our findings using unpublished individual patient data from two independent Oxford studies.

Findings

In OXVASC, detailed family history was available in 806 (93%) probands. Female probands were more likely than males to have at least one affected first-degree relative (146/423 vs 104/383; OR 1·4, 95% CI 1·1–2·0, p=0·02) due entirely to an excess of affected female relatives in female probands (female relative vs male relative OR=1·7, 1·3–2·4, p=0·0004; female only vs male only OR=2·1, 1·4–3·1, p=0·0001). Maternal stroke was more common than paternal stroke in female probands (OR=1·8, 1·2–2·7, p=0·001) but not in males (OR=1·1, 0·7–1·7, p=0·38), and female probands were more likely than males to have an affected sister (OR=3·1, 1·5–6·7, p=0·004) but not an affected brother (OR=1·1, 0·6–2·1, p=0·80). Ages at first stroke were also correlated within families among affected females (r=0·36, p=0·004) but not among affected males, such that the excess of affected female relatives of female probands was greatest when the difference in age at first stroke was less than 5 years (OR=3·7, 1·6–8·6, p=0·0007) and fell as the age difference increased (p for trend=0·004). These findings were independent of traditional risk factors and stroke subtype. Data from the other Oxford studies confirmed the excess maternal history of stroke in female probands (OR=2·3, 1·5–3·8, p<0·00001) and the lack in males (OR=1·0, 0·7–1·4, p=0·58).

Interpretation

Heritability of ischaemic stroke is greater in women than in men, with an excess of affected mothers and affected sisters in female probands independent of traditional vascular risk factors, which could be explained by sex-specific genetic, epigenetic, or non-genetic mechanisms.

Introduction

Stroke is the most important cause of disability worldwide.1 An increasing number of studies have shown that ischaemic stroke is, at least in part, a heritable disease.2, 3 However, the relative importance of genetic and environmental factors is uncertain. There are examples of mutations in specific genes that cause mendelian forms of ischemic stroke,3 but these mutations are rare and none of these contributes significantly to stroke risk in the general population. Some genetic polymorphisms have been associated with stroke, but the mechanisms remain to be determined and most subsequent studies have failed to replicate the findings.4 In fact, heritability of stroke could also be explained by inheritance of intermediate phenotypes, such as hypertension,5, 6 by gene–gene or gene–environment interactions,7, 8 or by exposure to environmental factors in early life.9

Family-history studies can be used to investigate the heritability of complex diseases, such as stroke, and potential interactions between genetic and environmental factors.10 Although the transmission of stroke in families is clearly not in accordance with a classic mode of genetic inheritance, very little attention has been paid to a possible differential transmission from mothers or fathers and to male or female offspring. Yet, this issue is important for three main reasons. First, there are differences between stroke in men and women in relation to risk factors, frequency of subtypes, and outcome, and so heritability cannot necessarily be assumed to be similar.11 Second, some genetic factors predisposing to stroke or to intermediate phenotypes might be linked to sex chromosomes or mitochondrial genetic defects. Third, several studies have suggested that the risk of future vascular disease and of development of vascular risk factors could be programmed during fetal life.9, 12, 13 An ecological correlation between low birthweight and risk of later coronary artery disease or stroke notably underlies this latter hypothesis.9, 12 Greater maternal-offspring than paternal-offspring transmission of type 2 diabetes is also well established and is associated with intrauterine exposure to diabetes.14 If such fetal programming occurs, then one would expect to observe a greater maternal-offspring than paternal-offspring association for stroke.

In the absence of any previous systematic studies or published data from large population-based studies, we determined the relation between the sex and phenotype of affected probands and history of stroke in mothers, fathers, and siblings in the Oxford Vascular study (OXVASC) of patients with ischaemic stroke or transient ischaemic attack. We then tested the validity of the OXVASC findings in unpublished individual patient data from two previous independent Oxford studies.

Section snippets

OXVASC data

The methods of the OXVASC study have been published previously.15 Briefly, OXVASC is a population-based study of all incident or recurrent transient ischaemic attacks and strokes in a population of 91 106 people registered with 63 family physicians in Oxfordshire, UK. The study conforms to the standard quality criteria for stroke incidence studies.16 Multiple search methods ensure near complete ascertainment of all cases.15 All patients with a diagnosis of ischaemic stroke or transient

Results

865 patients with an ischaemic stroke or a transient ischaemic attack were enrolled. Family history of stroke was not available for either parent for 59 (7%) patients (30 women), usually because the patient died before assessment without an informative relative (n=26) or because they did not know their family (n=19). Therefore, 806 patients (423 women, 383 men) were included in the present study (table 1). Compared with men, women were older, were slightly more likely to have had a transient

Discussion

We have shown that in addition to known differences between men and women with stroke and transient ischaemic attack, women are more likely than men to have a history of stroke in mothers than in fathers and in sisters than in brothers. We used data from OXVASC, a prospective population-based study with near-complete ascertainment in which we obtained a comprehensive family history. We confirmed our findings in two independent datasets. Using data from OXVASC, we have also shown that our

References (40)

  • BB Worall et al.

    PDE4D and stroke: a real advance or a case of the Emperor's new clothes?

    Stroke

    (2006)
  • E Flossmann et al.

    Family history of stroke in patients with transient ischemic attack in relation to hypertension and other intermediate phenotypes

    Stroke

    (2005)
  • E Flossmann et al.

    Potential confounding by intermediate phenotypes in studies of the genetics of ischaemic stroke

    Cerebrovasc Dis

    (2005)
  • A Pezzini et al.

    Cumulative effect of predisposing genotypes and their interaction with modifiable factors on the risk of ischemic stroke in young adults

    Stroke

    (2005)
  • Z Szolnoki et al.

    Evaluation of the interactions of common genetic mutations in stroke subtypes

    J Neurol

    (2002)
  • DJ Barker et al.

    Prenatal influences on stroke mortality in England and Wales

    Stroke

    (2003)
  • CD Bushnell et al.

    Advancing the study of stroke in women: summary and recommendations for future research from an NINDS-Sponsored Multidisciplinary Working Group

    Stroke

    (2006)
  • DJ Barker

    Fetal origins of coronary heart disease

    BMJ

    (1995)
  • JE Harding

    The nutritional basis of the fetal origins of adult disease

    Int J Epidemiol

    (2001)
  • AJ Karter et al.

    Excess maternal transmission of type 2 diabetes. The Northern California Kaiser Permanente Diabetes Registry

    Diabetes Care

    (1999)
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