The ANRIL Genetic Variants and Their Interactions with Environmental Risk Factors on Atherothrombotic Stroke in a Han Chinese Population.

BACKGROUND: Ischemic stroke (IS) is considered to be a heterogeneous, multifactorial disease with a strong genetic background. This study aims to determine whether variants in the antisense noncoding RNA in the INK4 locus (ANRIL) gene are associated with IS in Han Chinese, as well as whether there is evidence of a gene-environment interactions. MATERIALS AND METHODS: A case-controlled association study was conducted in which only patients with atherothrombotic stroke (ATS) were enrolled. Multifactor dimensionality reduction model was employed to screen the best interaction combinations among gene and environmental risk factors; RESULTS: A total of 405 subjects (200 cases and 205 controls) and 16 single nucleotide polymorphisms (SNPs) in ANRIL gene were included in this study. The 4 SNPs (rs1537378, rs2184061, rs7044859, and rs7865618) were found to be significantly related to ATS in Chinese Han nationality. In overall people or subjects aged 45 years or older, the GG genotype and G allele of rs1537378, the AA genotype and A allele of rs2184061 and rs7865618, and the AA genotype of rs7044859 increased the risk of ATS. In males, the GG genotype and G allele of rs1537378, the AA genotype and A allele of rs7865618, and the A allele of rs2184061 conferred a susceptibility to ATS. Additionally, the AAAGAGCAAAAAATAG haplotype exhibited an elevated risk of ATS, and a significant interaction was found in ATS susceptibility between ANRIL gene and dyslipidemia; CONCLUSIONS: The ANRIL gene was related to ATS susceptibility in a Han Chinese. Future studies should be performed with larger samples and among different ethnic populations.

Interactions among Variants in Eicosanoid Genes Increase Risk of Atherothrombotic Stroke in Chinese Populations.

BACKGROUND: Eicosanoids are lipid mediators that may play a role in ischemic stroke (IS). However, the association of variants in eicosanoid genes and these interactions with IS risk has not been investigated. The aim of the present study was to investigate the association of 11 variants in eicosanoid genes with IS and to determine whether these gene-gene interactions increase the risk of IS. METHODS: Eleven variants in prostaglandin H synthase-1 (PTGS1), PTGS2, thromboxane A2 synthase (TBXAS1), prostacyclin synthase (PTGIS), and prostaglandin E synthase (PTGES) genes were examined using mass spectrometry method in 297 patients with atherothrombotic stroke and 291 controls. Gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) method. Platelet aggregation and platelet-leukocyte aggregates were measured on admission. RESULTS: There were no significant differences in the genotype distributions of the 11 variants between patients and controls. However, GMDR analysis showed a significant gene-gene interaction among rs20417, rs5602, and rs41708, which scored 10 for cross-validation consistency and 9 for the sign test (P = .014). Logistic regression analysis showed that high-risk interaction among rs20417, rs5602, and rs41708 was an independent risk factor for atherothrombotic stroke (OR = 2.45, 95% CI: 1.33-3.27, P = .019). The high-risk interactive genotypes were associated with higher platelet aggregation and platelet-leukocyte aggregates. CONCLUSIONS: PTGS2 rs20417, PTGIS rs5602, and TBXAS1 rs41708 three-locus interactions may confer a higher risk for atherothrombotic stroke. The combinatorial analysis used in this study may be helpful to elucidate complex genetic risk for IS.

Clinical characteristics and prognosis of cerebral venous thrombosis in Chinese women during pregnancy and puerperium.

Due to the specific physiology associated with pregnancy and puerperium, cerebral venous sinus thrombosis (CVT) may manifest different characteristics. This study aimed to identify the clinical manifestations and prognosis of pregnancy-associated CVT. A total of 43 pregnancy-associated CVT patients were enrolled. We analysed the clinical presentations of the disease and performed a multivariate logistic regression analysis to determine which variables were associated with prognosis. Our descriptive results showed the following: 1) the incidence was 202 per 100,000 deliveries, and the mortality rate was 11.63%; 2) the most frequent symptom was headache; 3) the most frequent abnormal laboratory findings were increased levels of fibrinogen and several serum lipoproteins (including triglyceride, cholesterol, high-density lipoprotein, low-density lipoprotein, apolipoprotein A1, and apolipoprotein B); and 4) the superior sagittal sinus and transverse sinus were the most frequently affected locations. Moreover, an increased modified Rankin Scale score was positively associated with infection, seizure, intracerebral haemorrhage (ICH) and hypertensive disorders of pregnancy (HDP). Comparably, the occurrence of death was positively and significantly associated with infection, seizure and ICH. Consequently, timely diagnosis and treatment of pregnancy-associated CVT patients with infection, seizure, ICH or HDP are needed. Patients with infection, seizure or ICH have a greater risk of death.

Role of inflammatory parameters in the susceptibility of cerebral thrombosis.

We aimed to investigate the association of inflammation-related genes such as IL-10, IL-6 and IL-1B with risk of ischemic stroke. We included 426 cases with ischemic stroke and 426 health controls from Xinxiang, China. Genomic DNA was extracted from the buffy coat layer of collected blood with the TIANamp blood DNA kit. Diabetes, hypertension, obesity, and smoking habits were associated with risk of ischemic stroke. We found that individuals carrying the CC genotype of IL-1B rs1864169 had a higher risk of ischemic stroke when compared with the TT genotype (OR = 1.80, 95%CI = 1.16-2.80). The IL-6 rs1800796 TT genotype was associated with increased risk of ischemic stroke. We found that IL-1B rs1864169 and IL-6 rs1800796 polymorphisms may interact with diabetes, hypertension and obesity. Our study suggests that IL-6 rs1800796 and IL-1B rs1864169 polymorphisms are associated with ischemic stroke risk in the Chinese population.

Mortality in cerebral venous thrombosis: results from the national inpatient sample database.

BACKGROUND: Outcomes of cerebral venous thrombosis (CVT) vary from full recovery to death. Few studies have been performed examining epidemiologic and medical risk factors associated with high mortality in CVT. In this study, we examined the National Inpatient Sample (NIS) to determine the epidemiologic and medical risk factors associated with increased mortality from CVT. MATERIALS AND METHODS: Using the NIS from 2001 to 2008, patients who suffered from CVT were identified using the ICD-9 codes 437.6 (nonpyogenic thrombosis of intracranial venous sinus), 325 (phlebitis and thrombophlebitis of intracranial venous sinuses) and 671.5 (peripartum phlebitis and thrombosis, cerebral venous thrombosis, thrombosis of intracranial venous sinus). We analyzed the associations of demographic factors, risk factors, comorbidities, complications of CVT, and therapeutic interventions with in-hospital mortality. We performed a multivariate logistic regression analysis to determine which variables were independently associated with in-hospital mortality. RESULTS: 11,400 patients were hospitalized with CVT between 2001 and 2008. Two-hundred and thirty-two (2.0%) suffered in-hospital mortality. Patients 15-49 years old had the lowest mortality rate (1.5%) compared with 2.8% for patients aged 50-64 (p < 0.001) and 6.1% for patients ≥65 years old (p < 0.001). The most common condition associated with CVT was pregnancy/puerperium (24.6%), and these women had a low mortality rate (0.4%). On multivariate analysis, the comorbidity most strongly associated with increased risk of mortality was sepsis (mortality rate 15.6%, OR = 7.5, 95% CI = 4.79-11.53, p < 0.001). Malignancy, underlying autoimmune disease and substance abuse were also independently associated with mortality, but with lower mortality rates (<5%). Complications associated with increased risk of mortality included paralysis (8.0%, OR = 3.4, 95% CI = 3.17-6.96, p < 0.001), intracranial hemorrhage (8.7%, OR = 5.4, 95% CI = 4.38-7.96, p < 0.001), and hydrocephalus (15.0%, OR = 3.2, 95% CI = 5.54-15.11, p = 0.004). Demographic variables associated with decreased mortality on multivariate analysis were male gender (2.1%, OR = 0.62, 95% CI = 0.43-0.87, p = 0.006) and Asian/Pacific Islander race (OR = 0.00, 95% CI = 0-0.27, p < 001). CONCLUSIONS: CVT is associated with a low in-hospital mortality rate. Amongst patients suffering CVT, male gender and Asian/Pacific Islander race were independently associated with lower odds of in-hospital mortality when compared to their female and white counterparts, respectively. Septic patients with CVT have the greatest risk of in-hospital mortality. Hydrocephalus, intracranial hemorrhage, and motor deficits are also associated with higher risk of death. Our results build on previous evidence that serves to define a group of patients with CVT at high risk of early death.

Disparities in stroke type and vascular risk factors between 2 Hispanic populations in Miami and Mexico city.

BACKGROUND: The heterogeneous nature and determinants of stroke among different Hispanic groups was examined by comparing hospitalized Hispanic stroke patients in Miami, where the Hispanic population is largely of Caribbean origin, to a Mestizo population in Mexico City. METHODS: Consecutive Hispanic patients who were admitted with stroke or transient ischemic attack (TIA) and included in the prospective stroke registries of 2 tertiary care teaching hospitals were studied. Demographic factors, stroke subtypes, vascular risk factors, stroke severity, and outcomes were compared. Vascular risk factor definitions were standardized. RESULTS: A total of 928 patients (520 Mexicans and 408 Miami Hispanics) were analyzed. Mexicans were younger, with a greater proportion of women. More cerebral venous thromboses (CVTs) were admitted in Mexico, while TIA and stroke mimics were more commonly admitted in Miami; cardioembolic strokes were more commonly ascertained in Miami, and more cryptogenic strokes in Mexico. Stroke severity was similar for intracerebral hemorrhages, but more severe ischemic strokes and CVTs were included in the Mexican registry. Outcome at 1 and 3 months was similar in both registries after adjusting for age and baseline stroke severity. After adjusting for age and sex, hypertension, dyslipidemia, and atrial fibrillation were more frequent, and diabetes mellitus was less frequent, among Miami Hispanics compared to Mexicans. CONCLUSIONS: We found significant differences in the frequency of hypertension, diabetes, dyslipidemia, and atrial fibrillation in Miami Hispanics and Mexican stroke patients, highlighting the heterogeneity of the Hispanic ethnic group. Future studies are needed to clarify the relative contribution of genetic and environmental disparities amongst Mexican and Caribbean Hispanic stroke patients.

Predictors of cerebral venous thrombosis and arterial ischemic stroke in young Asian women.

The management and outcome of cerebral venous thrombosis (CVT) may be different from that of arterial ischemic stroke (AIS). Clinically differentiating the 2 diseases on clinical grounds may be difficult. The main objective of this study was to identify predictors differentiating CVT from AIS in a large cohort of young Asian women, based on risk factors and investigations. Twelve centers in 8 Asian countries participated. Women aged 15-45 years were included if they had a diagnosis of first-ever symptomatic AIS or CVT confirmed by brain computed tomography scan or magnetic resonance imaging/magnetic resonance venography. Patients with head trauma, cerebral contusions, intracranial hemorrhage, and subarachnoid or subdural hemorrhage were excluded. Data, including demographic data, risk factor assessment, neuroimaging studies, blood tests, and cardiac studies, were collected by retrospective and then prospective chart review between January 2001 and July 2008. Outcome was based on the modified Rankin Scale (mRS) score at admission, discharge, and latest follow-up. A total of 958 patients (204 with CVT and 754 with AIS) were included in the study. Age under 36 years, anemia, pregnancy or postpartum state, and presence of hemorrhagic infarcts on computed tomography scan or magnetic resonance imaging were significant predictors of CVT on univariate analysis. Age over 36 years, diabetes, hypertension, dyslipidemia, recent myocardial infarction, electrocardiogram abnormalities, and blood glucose level >150 mg/dL were strong predictors of AIS. On multivariate analysis, postpartum state and hemorrhagic infarct were the strongest predictors of CVT (P < .001). Mortality was comparable in the 2 patient groups. Prognosis was significantly better for patients with CVT than for those with AIS (mRS score 0-2, 74% v 46%; P < .001). There was no difference in outcome between patients with obstetric and nonobstetric CVT. Our data indicate that in young Asian women, predictors of CVT differ from those for AIS. These findings could be useful in the early identification and diagnosis of patients with CVT.

Ischemic stroke in young Asian women: risk factors, subtypes and outcome.

BACKGROUND AND OBJECTIVE: The objective of our study was to describe risk factors, mechanisms and outcome of young Asian women with ischemic stroke. METHODS: Twelve tertiary-care centers in 8 Asian countries participated. Women aged 15-45 years were included if they had an ischemic stroke supported by neuroimaging. Data on age, risk factor history, stroke mechanism and discharge status were collected. RESULTS: A total of 958 subjects were included, their mean age was 34 years. Large-vessel thrombosis comprised 24%, cerebral venous thrombosis 21%, cardioembolism 19% and small-vessel thrombosis 15%. The stroke risk factors included hypertension (29%), diabetes (14%), pregnancy (11%), valvular heart disease (10%) and cigarette smoking (3%). Anemia was found in 42%, and mortality was 4%; at discharge, 17% had modified Rankin score (mRS) >4 and 83% mRS 0-3. CONCLUSION: Unlike among Caucasians, large-vessel thrombosis, cerebral venous thrombosis and cardioembolism are common among young Asian women with stroke. A high proportion are pregnancy-related. More studies are needed.

Aspirin resistance in South African Caucasian patients with thrombotic cerebrovascular events.

OBJECTIVE: Stroke is the second commonest cause of death in both high and low- and middle-income countries [Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. The Lancet 2006; 367:1747-57]. In South Africa, a population undergoing demographic and epidemiological transition, stroke is the third commonest cause of death [Norman R, Bradshaw D, Schneider M, Pieterse D, Groenewald P. Revised burden of disease estimates for the comparative risk factor assessment, South Africa, 2000. Cape Town: Medical Research Council. 2006]. Although aspirin remains an essential part of stroke prevention, platelet response to therapeutic doses is not uniform. Some patients exhibit aspirin resistance and develop secondary thrombotic events. We decided to determine the prevalence of aspirin resistance and/or platelet hypersensitivity, as determined by platelet aggregometry, in sixty Caucasian patients who have suffered one or more Strokes and/or Transient Ischaemic Attacks (TIAs) as compared with sixty control subjects. METHODS: Aspirin resistance was determined by platelet aggregation (>20%) to one or more of the four agonists, namely arachidonic acid (1.5 mM), adrenaline (0.05 microg/ml), collagen (0.2 microg/ml) or ADP (0.1x10(-5) M). RESULTS: Two patients demonstrated "complete aspirin resistance" (non-responder to aspirin) with resistance to arachidonic acid (high concentration) noted. Three patients demonstrated "partial aspirin resistance" (semi-responder to aspirin). One contol subject showed "complete aspirin resistance". There is a 1.67% chance of a control subject being resistant to aspirin in a general South African Caucasian population. A history of prior stroke or transient ischaemic attack was associated with a statistically significant increase in risk of aspirin resistance with an odds ratio of 5.36. CONCLUSION: These results essentially concur with those of the studied literature in showing an 8% prevalence (statistically significant) of aspirin resistance (complete and partial) in South African Caucasian patients with previous atherothrombotic cerebrovascular events i.e. CVAs and/or TIAs. The current study shows an increased prevalence of aspirin resistance in people who have had prior strokes/TIAs and raises the question whether people who have had these events are somehow predisposed to vascular events or indeed recurrent vascular events. "Aspirin resistant" patients or "poor responders" to aspirin must be considered at heightened risk of atherothrombotic events and laboratory monitoring of antiplatelet therapy may become clinically useful.

Novel mutation in the ABCA1 gene identified in a chinese patient with dementia and atherothrombotic cerebral infarction.

BACKGROUND: To date, 81 mutations of ATP-binding cassette transporter 1 (ABCA1) have been reported. However, no ABCA1 mutation has been reported in the Chinese population. METHODS: We used direct sequencing to screen for ABCA1 mutations in 72 patients with both atherosclerotic cerebral infarction (ACI) and plasma high-density lipoprotein cholesterol (HDL-C) < 0.8 mmol/l. The functionality of the mutation was verified using 200 unrelated controls and 76 patients with ACI and normal HDL-C by PCR-RFLP analysis. RESULTS: One patient with dementia prior to ACI was found to carry the heterozygous Y2206D mutation, which has not been reported previously. The patient had a medical history of atherosclerosis in the coronary and carotid arteries going back 40 years and splenohepatomegalia for 13 years, with a low plasma HDL-C level (0.66 mmol/l) and apolipoprotein A1 level (0.61 mmol/l). During the past decade, he had developed symptoms of dementia. Sixteen months prior to the study, he was admitted to hospital for an ACI. CONCLUSION: The results suggest that this patient is most likely a patient with familial hypoalphalipoproteinemia and that the Y2206D mutation may be associated with not only a lower level of HDL-C, but also with dementia.

A561C polymorphism of E-selectin is associated with ischemic cerebrovascular disease in the Japanese population without diabetes mellitus and hypercholesterolemia.

E-selectin, which is a member of the selectin superfamily of adhesion molecules, contributes to the leukocyte-endothelial cell attachments and is involved in the pathogenesis of thrombovascular diseases as a consequence. We investigated the A561C mutation in the E-selectin gene in 235 Japanese patients with ischemic cerebrovascular disease (CVD) and 301 age- and sex-matched healthy controls. Excluding the subjects with diabetes mellitus and hypercholesterolemia, the AC genotype frequencies of patients with ischemic CVD were higher than those of controls: 12.7% vs. 5.8% (P=0.04). Our results show that E-selectin gene polymorphisms represent an increased risk for ischemic CVD in the Japanese population without diabetes mellitus and hypercholesterolemia.

Ethnic differences in cerebral venous thrombosis.

BACKGROUND: Cerebral venous thromboses (CVT) with distinct clinical presentations have been shown worldwide. However, there is little information regarding race-ethnic differences in this disease. METHODS: We prospectively studied 50 CVT patients from Brazil, comparing clinical and laboratory data among white (W) and African-Brazilian (AB) patients. RESULTS: Seventy percent of the patients were female, 26 W and 23 AB, mean age 34.7 years. Multiple sinus CVT, deep CVT and worse outcome were significantly more frequent in AB than in W patients. There was a trend towards a higher frequency of factor V Leiden and prothrombin mutation in W than in AB, and of protein C deficiency in AB. CONCLUSIONS: CVT was more severe in AB patients than in W patients. Race-ethnic differences may account for the heterogeneous distribution of inherited thrombophilia in this series.