Fast track — ArticlesHeritability of ischaemic stroke in women compared with men: a genetic epidemiological study
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
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