Evita G. Van Den Herik

Genomewide Association Studies of Stroke

BACKGROUND The genes underlying the risk of stroke in the general population remain undetermined. METHODS We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

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.

Newly-Diagnosed Disturbed Glucose Metabolism is Associated withAtherosclerosis in Patients with Transient Ischemic Attack or IschemicStroke

Objective: Newly-diagnosed disturbed glucose metabolism is highly prevalent in non-diabetic patients with transient ischemic attack (TIA) or ischemic stroke, and increases the risk of recurrent stroke. Diabetes mellitus is associated with atherosclerosis. We aimed to assess whether newly-diagnosed disturbed glucose metabolism is associated with atherosclerosis as well. Research design and methods: Patients with a recent TIA or ischemic stroke were classified in three groups based on glucose levels and use of antidiabetic drugs. Pre-existent diabetes mellitus was defined as the use of antidiabetic drugs prior to the event. Newly-diagnosed disturbed glucose metabolism was defined as two or more disturbed glucose tests: fasting plasma glucose level ≥ 5.6 mmol/L, 2-hour post-load glucose level ≥ 7.8 mmol/L, and/or glycosylated hemoglobin level ≥ 39 mmol/mol. We used CT-angiography to assess stenosis in the carotid artery bifurcations and calcification volume in the aortic arch, carotid bifurcations and intracranial carotid arteries. The relation between glucose groups and measures of atherosclerosis was expressed as odds ratios and beta coefficients with corresponding 95% CI, adjusted for potential confounders. Results: Of the 1217 patients, 384 (32%) had newly-diagnosed disturbed glucose metabolism, and 210 (17%) had pre-existent diabetes mellitus. Newly-diagnosed disturbed glucose metabolism was independently associated with stenosis ≥ 50% (aOR (95%CI) 1.15 (1.04-2.20)). Pre-existent diabetes mellitus was associated with stenosis ≥ 50% and with calcification volume in all regions, especially in patients without the use of cholesterol-lowering drugs prior to the event. Conclusions: Our study shows that newly-diagnosed disturbed glucose metabolism in patients with a recent TIA or ischemic stroke is associated with more severe extra- and intracranial atherosclerosis, similar to pre-existent diabetes mellitus.

Variation in the C-reactive protein gene is associated with serum levels of CRP in patients with acute ischemic stroke

Background and Purpose: Elevated levels of C-reactive protein (CRP) are found in up to three quarters of patients with acute ischemic stroke and are associated with poor outcome. We investigated whether haplotypes representing common variations in the CRP gene are associated with levels of CRP in patients with acute ischemic stroke. Methods: We included 185 patients with ischemic stroke in whom CRP was measured within 24 h of symptom onset. Common haplotypes within the CRP gene were determined by 3 genotype-tagging single-nucleotide polymorphisms (SNPs). Results: Four haplotypes with frequencies >5% covered 99.2% of the genetic variation. Haplotype 4 (CCG, frequency 8.3%) was associated with a 20.6 mg/l (95% CI, 9.8–30.4) stronger increase in CRP level as compared with haplotype 1 (CTC, frequency 33.7%). Conclusion: Variation in the CRP gene is associated with levels of CRP in acute ischemic stroke.

Predicting and preventing stroke after transient ischemic attack

The prognosis of transient ischemic attacks (TIAs) is not as favorable as previously thought. Given a risk of stroke of approximately 10% in the first week following a TIA, urgent evaluation and initiation of treatment are required. Recently developed scores to predict the early risk of subsequent stroke in individual patients may guide treatment decisions in the acute phase. Lately it has become clear that transient attacks with nonfocal symptoms are not benign either, as these were found to be associated with an increased risk of vascular disease. The significance of this finding and its implications for treatment are not yet clear. There is substantial evidence from a number of clinical trials that adequate secondary prevention therapies can reduce the risk of stroke after TIA. In addition to the conventional vascular risk factors, interest has grown in less strong but more prevalent lifestyle factors, but trials evaluating the effect of modifying these factors are as yet lacking.

Association of two single nucleotide polymorphisms from genomewide association studies with clinical phenotypes of cerebral ischemia

Background Recent genomewide association studies have revealed an association between two single nucleotide polymorphisms, rs11833579 and rs12425791, and ischemic stroke. Aim To gain more insight in pathophysiological mechanisms underlying the found associations by exploring relationships between these single nucleotide polymorphisms and clinical and radiological characteristics of patients with cerebral ischemia. Methods Our cohort consisted of 660 Caucasian patients with cerebral ischemia; from all patients detailed clinical and radiological data were available. Etiologic subtype of cerebral ischemia was determined according to the TOAST classification and an alternative classification. We studied associations between risk alleles and etiologic subtype, duration of ischemia, occurrence of multiple events, functional outcome and findings on CT-angiography by means of logistic regression analysis. Results The risk allele of rs11833579 was associated with an atherothrombotic etiology of cerebral ischemia, but not with other etiologic subtypes. Risk alleles of both single nucleotide polymorphisms were related to events of shorter duration (>24 ***h), the risk allele of rs11833579 with occurrence of multiple events. There was no association between single nucleotide polymorphism and clinical outcome. Both single nucleotide polymorphisms were associated with presence of stenotic calcifications and stenosis #<30% in a symptomatic artery on CT-angiography. Conclusions This is the first study to show an association of rs11833579 with multiple episodes of cerebral ischemia of atherothrombotic origin, and of rs11833579 and rs12425791 with short duration of ischemia. Also, we found an association of both single nucleotide polymorphisms with atherosclerotic lesions in the extracranial vessels on CT-angiography. Together this suggests a relationship between the two single nucleotide polymorphisms and large artery pathology.