Family History of Stroke Does Not Predict Risk of Stroke After Transient Ischemic Attack
Background and Purpose— Animal models suggest a genetic contribution to cerebral susceptibility to ischemia. Family history of stroke (FHxstroke) is a risk factor for ischemic stroke, but there is significant confounding by heritability of hypertension and other intermediate phenotypes, and it is uncertain whether genetic factors have a direct independent influence on cerebral susceptibility to ischemia in man.
Methods— We related detailed FHxstroke to baseline characteristics and subsequent risk of stroke in 2 population-based incidence studies and a consecutive hospital-referred series of patients with recent transient ischemic attack (TIA).
Results— In none of the cohorts or the pooled data (757 patients; 5515 patient years follow-up; 200 ischemic strokes; 126 myocardial infarctions [MIs]) did FHxstroke predict ischemic stroke (odds ratio [OR], 0.87; 95% CI, 0.57 to 1.32). No associations were revealed by analyses stratified by age or hypertension in the proband, FHxstroke in parents versus siblings, number of affected relatives, or their age at stroke. FHxstroke was unrelated to presence of ischemic lesions on baseline computed tomography (OR, 0.96; 0.52 to 1.76) or risk of MI during follow-up. There was no bias attributable to any relationship between FHxstroke and risk factor control or medication.
Conclusions— Family history of stroke does not predict risk of ischemic stroke after TIA.
Animal models and twin studies suggest that genes influence susceptibility to ischemic stroke, and there are some rare Mendelian stroke syndromes, as well as evidence of heritability of sporadic ischemic stroke in man.1,2 Genetic factors could influence susceptibility to stroke through intermediate phenotypes, such as hypertension and atherosclerosis,3 but might also influence cerebral susceptibility to ischemia (ie, for a given ischemic insult, the extent of brain injury could vary). Animal models show evidence of genetic variation in cerebral susceptibility to ischemia,4,5 but there is as yet little evidence in man.
Follow-up of transient ischemic attack (TIA) patients might provide insight into cerebral susceptibility to ischemia in man. First, the risk of stroke is high,6 allowing detailed clinical studies with sufficient statistical power. Second, the prospective design avoids the recall bias inherent in case-control studies. Third, biases attributable to missing data in patients with severe stroke are avoided, and potential confounding factors (eg, blood pressure, glucose) are measured more reliably. Fourth, because most TIA patients have vascular pathology, confounding by intermediate phenotypes should be reduced, allowing more reliable determination of factors that directly influence cerebral susceptibility. Yet, there has been only 1 study of the predictive value of family history of stroke (FHxstroke) in TIA patients.7 We therefore studied detailed FHxstroke in 2 population-based TIA cohorts8,9 and a consecutive hospital-referred series.10
The methods of all 3 cohorts have been published previously.6,8–11 Briefly, the Oxfordshire Community Stroke Project (OCSP) studied the incidence, risk factors, and outcome of incident TIA during 1981 to 1986.6 The ongoing Oxford Vascular Study (OXVASC) uses identical methods of ascertainment to the OCSP.8,9 For this report, we included patients with any TIA without previous stroke during 2002 to 2004.8 The Oxford hospital-referred TIA series was a consecutive prospective cohort of patients with incident TIA assembled during 1976 to 1986.10
We calculated odds ratios (ORs) within individual studies and combined them by fixed-effects Mantel–Haenszel meta-analysis. Heterogeneity between studies was calculated with the χ2 method. Where appropriate, data were pooled. To study differences in baseline characteristics, we used the χ2 test for categorical variables and ANOVA for continuous variables. For any factor that showed an association with FHxstroke, we performed a logistic regression analysis, adjusting for age, sex, and study. ORs conferred by FHxstroke were calculated by multivariate binary regression analysis adjusting for study, age, sex, treated hypertension, cerebral versus ocular TIA, diabetes, atrial fibrillation, smoking, and baseline systolic and diastolic blood pressure. We reassessed antithrombotic drug use, blood pressure, and blood lipids at follow-up to test for possible bias attributable to differential treatment or control of risk factors in relation to FHxstroke.
Of 209 TIA patients in OCSP and 175 in OXVASC, FHxstroke was available in 202 (96.7%) and 164 (93.7%), respectively. Of 469 patients from the hospital-referred series, FHxstroke was available in 391 after exclusion of patients coenrolled in the OCSP. Baseline characteristics are given in Table 1. FHxstroke was most common in women (P=0.013), in patients with treated hypertension (P=0.003), and with cerebral TIA (P=0.06). Subsequent analyses are thus adjusted for these differences or stratified appropriately. The proportions of patients with any ischemic lesion on computed tomography (CT) and the proportion with a lesion compatible with the presenting symptoms were unrelated to FHxstroke.
A total of 200 (26%) patients had an ischemic stroke, and 126 (17%) had a myocardial infarction (MI) during 5515 patient years of follow-up (OCSP 1411; OXVASC 201; hospital-referred series 3903). FHxstroke did not predict ischemic stroke in any cohort (Figure) or the pooled analysis (OR stratified by study, 0.97; 95% CI, 0.65 to 1.45; P=0.88; multivariate adjusted OR, 0.86; 0.57 to 1.31; P=0.48). No association was found in subgroup analysis by age (10-year bands), sex, history of hypertension, systolic blood pressure, ocular versus cerebral TIA, and whether parents or siblings were affected, and there was no clear increase in risk in patients with >1 affected first-degree relatives (FDRs) versus the remainder (adjusted OR, 1.26; 0.56 to 2.83; P=0.57; n=32). There was no association between age of affected FDRs at their stroke (mean=74 years) and risk of stroke in the proband (P=0.72) and no evidence that FHxstroke increased the risk of stroke in the first 90 days (adjusted OR, 0.56; 0.28 to 1.09; P=0.09). In none of the studies or the pooled data (adjusted OR, 1.35; 0.84 to 2.17; P=0.21) was FHxstroke related to the risk of MI (Figure).
In patients with a recent TIA, FHxstroke correlated with treated hypertension but did not predict appropriately located ischemic lesions on cerebral CT or the risk of subsequent stroke. These results will be useful in counseling TIA patients and show that risk of ischemic stroke after TIA is not highly heritable.
A study of heritability of stroke after TIA has the advantages outlined in the introduction, but our study does have some potential shortcomings. First, patient-reported FHxstroke is sometimes inaccurate. Nevertheless, it has good discriminatory power.12 Second, in common with previous studies, we had no information on the stroke subtype in the FDRs. Studies of affected sib-pairs enable detailed examination of relatives, but it would be difficult to assemble a large enough cohort of sib-pairs with TIA to study cerebral susceptibility. We were also unable to stratify results by underlying etiological subtype in the proband.13 However, our observations suggest that any effects in specific subtypes are unlikely to be large. Third, it is possible that the presence of FHxstroke increased the likelihood of diagnosis of TIA. However, diagnoses were made by vascular neurologists according to strict criteria, and the proportion of patients with appropriately located lesions on CT was unrelated to FHxstroke. Fourth, factors determining susceptibility to TIA might be similar to those for susceptibility to stroke, and we have not studied the hypothetical group of individuals who do not have a TIA despite having microemboli. Fifth, the included studies varied in the available length of follow-up. Also, whereas the population-based studies included the high-risk period of stroke immediately after a TIA, this period was not covered by the hospital-based cohort, explaining the different rates of strokes between the studies. However, our results were highly consistent in all 3 studies, and there was also no significant difference between early and late strokes.
E.F. and P.M.R. are funded by the United Kingdom Medical Research Council. We thank Professor Charles Warlow and the Oxford Community Stroke Project collaborators for allowing us access to their data. We are very grateful to our OXVASC collaborators for their help with this study.
- Received October 11, 2005.
- Revision received November 9, 2005.
- Accepted November 16, 2005.
Markus H. Stroke Genetics (chapters 3–8). Oxford, UK: University Press; 2003.
Flossmann E, Schulz UGR, Rothwell PM. Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke. 2004; 35: 212–227.
Flossmann E, Rothwell PM. Family history of stroke in patients with transient ischemic attack in relation to hypertension and other intermediate phenotypes. Stroke. 2005; 36: 830–835.
Coyle P, Jokelainen PT. Differential outcome to middle cerebral artery occlusion in spontaneously hypertensive stroke-prone rats and Wistar Kyoto rats. Stroke. 1983; 14: 605–611.
Lovett JK, Dennis MS, Sandercock PAG, Bamford J, Warlow CP, Rothwell PM. Very early risk of stroke after a first transient ischemic attack. Stroke. 2003; 34: 138–140.
Brass LM, Shaker LA. Family history in patients with transient ischemic attacks. Stroke. 1991; 22: 837–841.
Rothwell PM, Coull AJ, Giles MF, Howard SC, Silver LE, Bull LM, Gutnikov SA, Edwards P, Mant D, Sackley CM, Farmer A, Sandercock PA, Dennis MS, Warlow CP, Bamford JM, Anslow P; Oxford Vascular Study. Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study). Lancet. 2004; 363: 1925–1933.
Dennis MS, Bamford JM, Sandercock PA, Warlow CP. Incidence of transient ischemic attacks in Oxfordshire, England. Stroke. 1989; 20: 333–339.
Hankey GJ, Slattery JM, Warlow CP. The prognosis of hospital-referred transient ischemic attacks. J Neurol Neurosurg Psychiatry. 1991; 54: 793–802.
Clark TG, Murphy MFG, Rothwell PM. Long term risks of stroke, myocardial infarction, and vascular death in “low risk” patients with a non-recent TIA. J Neurol Neurosurg Psychiatry. 2003; 74: 577–580.
Schulz UGR, Flossmann E, Rothwell PM. Heritability of ischemic stroke in relation to age, vascular risk factors, and subtypes of incident stroke in population-based studies. Stroke. 2004; 35: 819–824.