John W. Cole

Probable Migraine With Visual Aura and Risk of Ischemic Stroke: The Stroke Prevention in Young Women Study

Background and Purpose— Migraine with aura is associated with ischemic stroke, but few studies have investigated the clinical and anatomic features of this association. We assessed the association of probable migraine with and without visual aura with ischemic stroke within subgroups defined by stroke subtype, vascular territory, probable migraine characteristics, and other clinical features. Methods— Using data from a population-based, case-control study, we studied 386 women ages 15 to 49 years with first ischemic stroke and 614 age- and ethnicity-matched controls. Based on their responses to a questionnaire on headache symptoms, subjects were classified as having no migraine, probable migraine without visual aura, or probable migraine with visual aura (PMVA). Results— Women with PMVA had 1.5 greater odds of ischemic stroke (95% CI, 1.1 to 2.0); the risk was highest in those with no history of hypertension, diabetes, or myocardial infarction compared to women with no migraine. Women with PMVA who were current cigarette smokers and current users of oral contraceptives had 7.0-fold higher odds of stroke (95% CI, 1.3 to 22.8) than did women with PMVA who were nonsmokers and non–oral contraceptive users. Women with onset of PMVA within the previous year had 6.9-fold higher adjusted odds of stroke (95% CI, 2.3 to 21.2) compared to women with no history of migraine. Conclusions— PMVA was associated with an increased risk of stroke, particularly among women without other medical conditions associated with stroke. Behavioral risk factors, specifically smoking and oral contraceptive use, markedly increased the risk of PMVA, as did recent onset of PMVA.

Sequence variants on chromosome 9p21.3 confer risk for atherosclerotic stroke.

Recent studies have identified a major locus for risk for coronary artery disease and myocardial infarction on chromosome 9p21.3. Stroke, in particular, ischemic stroke caused by atherosclerotic disease, shares common mechanisms with myocardial infarction. We investigated whether the 9p21 region contributes to ischemic stroke risk.

The Gene, Environment Association Studies Consortium (GENEVA): Maximizing the Knowledge Obtained from GWAS by Collaboration Across Studies of Multiple Conditions

Genome‐wide association studies (GWAS) have emerged as powerful means for identifying genetic loci related to complex diseases. However, the role of environment and its potential to interact with key loci has not been adequately addressed in most GWAS. Networks of collaborative studies involving different study populations and multiple phenotypes provide a powerful approach for addressing the challenges in analysis and interpretation shared across studies. The Gene, Environment Association Studies (GENEVA) consortium was initiated to: identify genetic variants related to complex diseases; identify variations in gene‐trait associations related to environmental exposures; and ensure rapid sharing of data through the database of Genotypes and Phenotypes. GENEVA consists of several academic institutions, including a coordinating center, two genotyping centers and 14 independently designed studies of various phenotypes, as well as several Institutes and Centers of the National Institutes of Health led by the National Human Genome Research Institute. Minimum detectable effect sizes include relative risks ranging from 1.24 to 1.57 and proportions of variance explained ranging from 0.0097 to 0.02. Given the large number of research participants (N>80,000), an important feature of GENEVA is harmonization of common variables, which allow analyses of additional traits. Environmental exposure information available from most studies also enables testing of gene‐environment interactions. Facilitated by its sizeable infrastructure for promoting collaboration, GENEVA has established a unified framework for genotyping, data quality control, analysis and interpretation. By maximizing knowledge obtained through collaborative GWAS incorporating environmental exposure information, GENEVA aims to enhance our understanding of disease etiology, potentially identifying opportunities for intervention. Genet. Epidemiol. 34: 364–372, 2010.

Smoking and stroke: the more you smoke the more you stroke

Cigarette smoking is a well-established risk factor for all forms of stroke. While both the general public and the global healthcare system are aware of the vascular risks associated with smoking, the prevalence of tobacco use has remained largely unchanged over the last quarter of a century. Approximately one in five US adults are classified as regular smokers, with the initiation of smoking typically occurring during the teenage years. Although the increased risk of stroke associated with smoking is generally acknowledged, it is less well recognized that considerable scientific evidence implicates a strong dose–response relationship between smoking and stroke risk. In this article, we summarize the literature regarding smoking-related stroke risk, the dose–response relationship, and the costs of this detrimental habit to both the individual and society as a whole.

Acquired Immunodeficiency Syndrome and the Risk of Stroke

Background and Purpose— Although acquired immunodeficiency syndrome (AIDS) is thought to increase the risk of stroke, few data exist to quantify this risk. This is the first population-based study to quantify the AIDS-associated risk of stroke. Methods— We identified all incident ischemic stroke (IS) and intracerebral hemorrhage (ICH) cases among young adults 15 to 44 years of age in central Maryland and Washington, DC, who were discharged from any of the 46 hospitals in the study area in 1988 and 1991. Using data from the medical records, 2 neurologists reviewed each case to confirm the diagnosis. Cases of AIDS among these patients with stroke were defined using Centers for Disease Control and Prevention criteria (1987). The number of cases of AIDS in the central Maryland and Washington population during 1988 and 1991 was determined from regional health departments working with the Centers for Disease Control and Prevention. Poisson regression was used to estimate the age-, race-, and sex-adjusted relative risk of stroke associated with AIDS. Results— There were 385 IS cases (6 with AIDS) and 171 ICH cases (6 with AIDS). The incidences of IS and ICH among persons with AIDS were both 0.2% per year. AIDS conferred an adjusted relative risk of 13.7 (95% confidence interval [CI], 6.1 to 30.8) for IS and 25.5 (95% CI, 11.2 to 58.0) for ICH. After exclusion of 5 cases of stroke in AIDS patients in whom other potential causes were identified, AIDS patients continued to have an increased risk of stroke with an adjusted relative risk of 9.1 (95% CI, 3.4 to 24.6) for IS and 12.7 (95% CI, 4.0 to 40.0) for ICH. Conclusions— This population-based study found that AIDS is strongly associated with both IS and ICH.

Common variants at 6p21.1 are associated with large artery atherosclerotic stroke

Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10−8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10−4; discovery and replication combined OR = 1.21, P = 4.7 × 10−8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.

Preeclampsia and the Risk of Ischemic Stroke Among Young Women Results From the Stroke Prevention in Young Women Study

Background and Purpose— Preeclampsia is a pregnancy-specific systemic syndrome of unknown cause that affects 3% to 8% of pregnancies in the United States. Although preeclampsia is known to be an important risk factor for pregnancy-associated stroke, few data exist with regard to its association with stroke not occurring during pregnancy or the postpartum period. Methods— Using data from the Stroke Prevention in Young Women Study (SPYW), a population-based case-control study of risk factors for ischemic stroke in women aged 15 to 44 years (recruitment period: 1992 to 1996, SPYW-1; 2001 to 2003, SPYW-2), we examined the independent association between a history of preeclampsia and the likelihood of ischemic stroke. Odds ratios (ORs) and 95% CIs were estimated using logistic regression. Cases (n=261) were women with stroke in the greater Baltimore-Washington area, and controls (n=421) were women free of a history of stroke identified by random digit dialing. Women who were pregnant at the time of stroke, those whose stroke occurred within 42 days postpartum, and nulligravida women were excluded from the analysis. Results— The prevalence of preeclampsia among cases and controls was 15% (SPYW-1: 16%; SPYW-2: 15%) and 10% (SPYW-1: 10%; SPYW-2: 11%), respectively. Preeclampsia was associated with an increased likelihood of ischemic stroke (crude OR: 1.59; 95% CI: 1.00 to 2.52). After multivariable adjustment for age, race, education, and number of pregnancies, women with a history of preeclampsia were 60% more likely to have a nonpregnancy-related ischemic stroke than those without a history of preeclampsia (OR: 1.63; 95% CI: 1.02 to 2.62). Similar patterns were observed for women who reported symptoms of preeclampsia (elevated blood pressure and proteinuria). Conclusion— These results suggest an association between a history of preeclampsia and ischemic stroke remote from pregnancy. If these results are confirmed in other studies, evaluation of the importance of targeting women with preeclampsia for close risk factor monitoring and control beyond the postpartum period may be warranted.

Dose-Response Relationship Between Cigarette Smoking and Risk of Ischemic Stroke in Young Women

Background and Purpose— Although cigarette smoking is known to be a risk factor for ischemic stroke, there are few data on the dose-response relationship between smoking and stroke risk in a young ethnically diverse population. Methods— We used data from the Stroke Prevention in Young Women Study, a population-based case-control study of risk factors for ischemic stroke in women aged 15 to 49 years to examine the relationship between cigarette smoking and ischemic stroke. Historical data, including smoking history, was obtained through standardized interviews. Odds ratios (OR) were estimated using logistic regression. Cases (n=466) were women with stroke in the greater Baltimore-Washington area, and controls (n=604) were women free of a stroke history identified by random digit dialing. Results— After multivariable adjustment, the OR comparing current smokers to never smokers was 2.6 (P<0.0001); no difference in stroke risk was observed between former smokers and never smokers. Adjusted OR increased with increasing number of cigarettes smoked per day (OR=2.2 for 1 to 10 cigs/d; 2.5 for 11 to 20 cigs/d; 4.3 for 21 to 39 cigs/d; 9.1 for 40 or more cigs/d). Conclusion— These results suggest a strong dose-response relationship between cigarette smoking and ischemic stroke risk in young women and reinforce the need for aggressive smoking cessation efforts in young adults.

Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection

Spontaneous intracranial artery dissection is an uncommon and probably underdiagnosed cause of stroke that is defined by the occurrence of a haematoma in the wall of an intracranial artery. Patients can present with headache, ischaemic stroke, subarachnoid haemorrhage, or symptoms associated with mass effect, mostly on the brainstem. Although intracranial artery dissection is less common than cervical artery dissection in adults of European ethnic origin, intracranial artery dissection is reportedly more common in children and in Asian populations. Risk factors and mechanisms are poorly understood, and diagnosis is challenging because characteristic imaging features can be difficult to detect in view of the small size of intracranial arteries. Therefore, multimodal follow-up imaging is often needed to confirm the diagnosis. Treatment of intracranial artery dissections is empirical in the absence of data from randomised controlled trials. Most patients with subarachnoid haemorrhage undergo surgical or endovascular treatment to prevent rebleeding, whereas patients with intracranial artery dissection and cerebral ischaemia are treated with antithrombotics. Prognosis seems worse in patients with subarachnoid haemorrhage than in those without.

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69–0.82; P = 4.46 × 10−10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10−3; combined P = 1.00 × 10−11). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.