Hongye Zhang

RISK FACTORS FOR ISCHAEMIC AND INTRACEREBRAL HAEMORRHAGIC STROKE IN 22 COUNTRIES (THE INTERSTROKE STUDY): A CASE-CONTROL STUDY

BACKGROUND The contribution of various risk factors to the burden of stroke worldwide is unknown, particularly in countries of low and middle income. We aimed to establish the association of known and emerging risk factors with stroke and its primary subtypes, assess the contribution of these risk factors to the burden of stroke, and explore the differences between risk factors for stroke and myocardial infarction. METHODS We undertook a standardised case-control study in 22 countries worldwide between March 1, 2007, and April 23, 2010. Cases were patients with acute first stroke (within 5 days of symptoms onset and 72 h of hospital admission). Controls had no history of stroke, and were matched with cases for age and sex. All participants completed a structured questionnaire and a physical examination, and most provided blood and urine samples. We calculated odds ratios (ORs) and population-attributable risks (PARs) for the association of all stroke, ischaemic stroke, and intracerebral haemorrhagic stroke with selected risk factors. FINDINGS In the first 3000 cases (n=2337, 78%, with ischaemic stroke; n=663, 22%, with intracerebral haemorrhagic stroke) and 3000 controls, significant risk factors for all stroke were: history of hypertension (OR 2.64, 99% CI 2.26-3.08; PAR 34.6%, 99% CI 30.4-39.1); current smoking (2.09, 1.75-2.51; 18.9%, 15.3-23.1); waist-to-hip ratio (1.65, 1.36-1.99 for highest vs lowest tertile; 26.5%, 18.8-36.0); diet risk score (1.35, 1.11-1.64 for highest vs lowest tertile; 18.8%, 11.2-29.7); regular physical activity (0.69, 0.53-0.90; 28.5%, 14.5-48.5); diabetes mellitus (1.36, 1.10-1.68; 5.0%, 2.6-9.5); alcohol intake (1.51, 1.18-1.92 for more than 30 drinks per month or binge drinking; 3.8%, 0.9-14.4); psychosocial stress (1.30, 1.06-1.60; 4.6%, 2.1-9.6) and depression (1.35, 1.10-1.66; 5.2%, 2.7-9.8); cardiac causes (2.38, 1.77-3.20; 6.7%, 4.8-9.1); and ratio of apolipoproteins B to A1 (1.89, 1.49-2.40 for highest vs lowest tertile; 24.9%, 15.7-37.1). Collectively, these risk factors accounted for 88.1% (99% CI 82.3-92.2) of the PAR for all stroke. When an alternate definition of hypertension was used (history of hypertension or blood pressure >160/90 mm Hg), the combined PAR was 90.3% (85.3-93.7) for all stroke. These risk factors were all significant for ischaemic stroke, whereas hypertension, smoking, waist-to-hip ratio, diet, and alcohol intake were significant risk factors for intracerebral haemorrhagic stroke. INTERPRETATION Our findings suggest that ten risk factors are associated with 90% of the risk of stroke. Targeted interventions that reduce blood pressure and smoking, and promote physical activity and a healthy diet, could substantially reduce the burden of stroke. FUNDING Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Pfizer Cardiovascular Award, Merck, AstraZeneca, and Boehringer Ingelheim.

Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study

BACKGROUND Stroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifiable risk factors for stroke in different regions of the world, and in key populations and primary pathological subtypes of stroke. METHODS We completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute first stroke (within 5 days of symptom onset and 72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke, and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks (PARs) were calculated, with 99% confidence intervals. FINDINGS Between Jan 11, 2007, and Aug 8, 2015, 26 919 participants were recruited from 32 countries (13 447 cases [10 388 with ischaemic stroke and 3059 intracerebral haemorrhage] and 13 472 controls). Previous history of hypertension or blood pressure of 140/90 mm Hg or higher (OR 2·98, 99% CI 2·72-3·28; PAR 47·9%, 99% CI 45·1-50·6), regular physical activity (0·60, 0·52-0·70; 35·8%, 27·7-44·7), apolipoprotein (Apo)B/ApoA1 ratio (1·84, 1·65-2·06 for highest vs lowest tertile; 26·8%, 22·2-31·9 for top two tertiles vs lowest tertile), diet (0·60, 0·53-0·67 for highest vs lowest tertile of modified Alternative Healthy Eating Index [mAHEI]; 23·2%, 18·2-28·9 for lowest two tertiles vs highest tertile of mAHEI), waist-to-hip ratio (1·44, 1·27-1·64 for highest vs lowest tertile; 18·6%, 13·3-25·3 for top two tertiles vs lowest), psychosocial factors (2·20, 1·78-2·72; 17·4%, 13·1-22·6), current smoking (1·67, 1·49-1·87; 12·4%, 10·2-14·9), cardiac causes (3·17, 2·68-3·75; 9·1%, 8·0-10·2), alcohol consumption (2·09, 1·64-2·67 for high or heavy episodic intake vs never or former drinker; 5·8%, 3·4-9·7 for current alcohol drinker vs never or former drinker), and diabetes mellitus (1·16, 1·05-1·30; 3·9%, 1·9-7·6) were associated with all stroke. Collectively, these risk factors accounted for 90·7% of the PAR for all stroke worldwide (91·5% for ischaemic stroke, 87·1% for intracerebral haemorrhage), and were consistent across regions (ranging from 82·7% in Africa to 97·4% in southeast Asia), sex (90·6% in men and in women), and age groups (92·2% in patients aged ≤55 years, 90·0% in patients aged >55 years). We observed regional variations in the importance of individual risk factors, which were related to variations in the magnitude of ORs (rather than direction, which we observed for diet) and differences in prevalence of risk factors among regions. Hypertension was more associated with intracerebral haemorrhage than with ischaemic stroke, whereas current smoking, diabetes, apolipoproteins, and cardiac causes were more associated with ischaemic stroke (p<0·0001). INTERPRETATION Ten potentially modifiable risk factors are collectively associated with about 90% of the PAR of stroke in each major region of the world, among ethnic groups, in men and women, and in all ages. However, we found important regional variations in the relative importance of most individual risk factors for stroke, which could contribute to worldwide variations in frequency and case-mix of stroke. Our findings support developing both global and region-specific programmes to prevent stroke. FUNDING Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland (Sweden), AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network.

Rationale and Design of INTERSTROKE: A Global Case-Control Study of Risk Factors for Stroke

Stroke is a major global health problem. It is the third leading cause of death and the leading cause of adult disability. INTERHEART, a global case-control study of acute myocardial infarction in 52 countries (29,972 participants), identified nine modifiable risk factors that accounted for >90% of population-attributable risk. However, traditional risk factors (e.g. hypertension, cholesterol) appear to exert contrasting risks for stroke compared with coronary heart disease, and the etiology of stroke is far more heterogeneous. In addition, our knowledge of risk factors for stroke in low-income countries is inadequate, where a very large burden of stroke occurs. Accordingly, a similar epidemiological study is required for stroke, to inform effective population-based strategies to reduce the risk of stroke. Methods: INTERSTROKE is an international, multicenter case-control study. Cases are patients with a first stroke within 72 h of hospital presentation in whom CT or MRI is performed. Proxy respondents are used for cases unable to communicate. Etiological and topographical stroke subtype is documented for all cases. Controls are hospital- and community-based, matched for gender, ethnicity and age (±5 years). A questionnaire (cases and controls) is used to acquire information on known and proposed risk factors for stroke. Cardiovascular (e.g. blood pressure) and anthropometric (e.g. waist-to-hip ratio) measurements are obtained at the time of interview. Nonfasting blood samples and random urine samples are obtained from cases and controls. Study Significance: An effective global strategy to reduce the risk of stroke mandates systematic measurement of the contribution of the major vascular risk factors within defined ethnic groups and geographical locations.

Hypertension prevalence, awareness, treatment, and control in 115 rural and urban communities involving 47 000 people from China.

Background: Identification and treatment of hypertension in China remain suboptimal despite high prevalence of hypertension and increasing incidence of stroke and myocardial infarction. Objective: This study reported blood pressure levels, prevalence, awareness, treatment, and control rates of hypertension, in addition to drug treatments in China. Methods: This is a country-specific analysis of 45 108 individuals, average age 51.4 (standard deviation 9.6) (35–70) years, enrolled between 2005 and 2009, from 70 rural and 45 urban communities in 12 provinces. Results: Among 18 915 (41.9% overall population) hypertensive participants, 7866 (41.6%) were aware, 6503 (34.4%) treated but only 1545 (8.2%) controlled. Prevalence of hypertension was higher, but awareness, treatment, and control were lower in rural than urban residents. Prevalence of hypertension was highest in eastern (44.3%), intermediate in central (39.3%), and lowest in western regions (37.0%). Awareness was higher in central (44.3%) and eastern (42.4%) but lower in western regions (37.0%). Similar patterns were observed in treatment rates, 37.7% central, 35.2% eastern, and 26.7% in western regions with control rates of 8.3% in eastern, 7.6% central, and 5.3% west regions. Of 4744 participants receiving documented treatments, 37.5% received traditional combination drugs alone, 55.4% western drugs alone and 7.1% combination of traditional combination drug in addition to western drugs. Conclusion: In China, hypertension is common, and while recent studies suggest some improvements, more than half of affected individuals were unaware that they had hypertension. Rates of control remain low. National programs effective in preventing and controlling hypertension in China are urgently needed.

Association of inflammatory gene polymorphisms with ischemic stroke in a Chinese Han population

BackgroundInflammatory mechanisms are important in stroke risk, and genetic variations in components of the inflammatory response have been implicated as risk factors for stroke. We tested the inflammatory gene polymorphisms and their association with ischemic stroke in a Chinese Han population.MethodsA total of 1,124 ischemic stroke cases and 1,163 controls were genotyped with inflammatory panel strips containing 51 selected inflammatory gene polymorphisms from 35 candidate genes. We tested the genotype-stroke association with logistic regression model.ResultsWe found two single nucleotide polymorphisms (SNPs) in CCL11 were associated with ischemic stroke. After adjusting for multiple testing using false discovery rate (FDR) with a 0.20 cut-off point, CCL11 rs4795895 remained statistically significant. We further stratified the study population by their hypertension status. In the hypertensive group, CCR2 rs1799864, CCR5 rs1799987 and CCL11 rs4795895 were nominally associated with increased risk of stroke. In the non-hypertensive group, CCL11 rs3744508, LTC4S rs730012, FCER1B rs569108, TGFB1 rs1800469, LTA rs909253 and CCL11 rs4795895 were associated with ischemic stroke. After correction for multiple testing, CCR2 rs1799864 and CCR5 rs1799987 remained significant in the hypertensive group, and CCL11 rs3744508, LTC4S rs730012, FCER1B rs569108, TGFB1 rs1800469, LTA rs909253 remained significant in the non-hypertensive group.ConclusionsOur results indicate that inflammatory genetic variants are associated with increased risk of ischemic stroke in a Chinese Han population, particularly in non-hypertensive individuals.

The rs10947803 SNP of KCNK17 is associated with cerebral hemorrhage but not ischemic stroke in a Chinese population

KCNK17 (potassium channel, subfamily K, member17) was first discovered to associate with the pathogenesis of ischemic stroke in the first genome-wide association study. The rs10947803 SNP in KCNK17 is significantly associated with ischemic stroke in Caucasian populations. The aim of the present study was to investigate the association with strokes in the Chinese population. A total of 1364 stroke patients and 1293 controls were examined using a case-control methodology. The rs10947803 SNP in KCNK17 was genotyped by a TaqMan real-time PCR assay. The rs10947803 SNP (A allele) of KCNK17 was significantly associated with cerebral hemorrhage (for AA+AC versus CC, unadjusted odds ratio [OR]=1.70; 95% confidence interval [CI], 1.08-2.69; P=0.020). After adjustment for age and sex, the association remained significant for AA+AC versus CC, OR=1.65; 95% CI, 1.04-2.62; P=0.033. In addition, the rs10947803 SNP in KCNK17 was not associated with ischemic stroke (for AA+AC versus CC, unadjusted OR=0.92; 95% CI, 0.81-1.05; P=0.212, after age- and sex-adjustment, OR=0.87; 95% CI, 0.72-1.05; P=0.143). The rs10947803 SNP (A allele) in KCNK17 increases the risk of cerebral hemorrhage but not ischemic stroke in the Chinese population.

Association of ABCG2 polymorphisms with ischemic stroke in a Chinese population

ATP‐binding cassette, superfamily G, member 2 (ABCG2) has been shown to play an important role in the development of ischemic stroke in European and African American populations. The aim of the present study is to test the hypothesis that there are associations between ABCG2 polymorphisms and ischemic stroke risk in a Chinese population. We conducted a case–control study including 967 participants with ischemic stroke and 939 stroke‐free controls. The rs2231137C > T and rs2231142G > T were genotyped using a TaqMan real‐time polymerase chain reaction assay. We found the rs2231137C > T and rs2231142G > T in ABCG2 were significantly associated with ischemic stroke (sex‐, age‐, BMI‐, SBP‐, DBP‐adjusted OR = 1.252; 95% CI, 1.035–1.515; P‐value = 0.021 and OR = 1.526; 95% CI, 1.085–2.146; P‐value = 0.015, respectively). By haplotype analyses, the haplotype T‐G still had a strongly significant association with ischemic stroke (OR = 0.806; 95% CI, 0.692–0.939; P‐value = 0.00568). Our findings identified the rs2231137C > T and rs2231142G > T polymorphisms of the ABCG2 as risk factors for ischemic stroke in a Chinese population.

APSH YI-02 THE POLYMORPHISM IN ALDEHYDE DEHYDROGENASE-2 (ALDH2) GENE IS ASSOCIATED WITH MYOCARDIAL INFARCTION AND STROKE IN A CHINESE POPULATION

Objective: Objective: Alcohol consumption has an important effect on coronary atherosclerotic heart disease (CAD). Acetaldehyde dehydrogenase 2 (ALDH2) is a key enzyme in alcohol metabolism. A G-to-A missense mutation of ALDH2 gene, rs671, which causes a Glu > Lys (504) substitution, was performed to detect the association with CAD and other relative diseases, but the results were not conclusive. The purpose of the present study was to determine whether this locus confers significant susceptibility to myocardial infarction and stroke in a Chinese population. Design and method: We conducted two case–control association studies (one cohort of 2325 myocardial infarction patients and 2620 unrelated controls, another cohort of 3960 stroke patients and 3654 controls)from the Chinese population. Genotyping of the rs671 SNP was performed by the TaqMan Real Time PCR method. Results: We found that rs671 (G allele) was significantly associated with myocardial infarction (odds ratio 1.21, 95% CI: 1.088–1.337, p = 0.00027, additive model), and logistic regression result indicated that the polymorphism was not associated with alcohol consumption and other risk factors. However, rs 671 (G allele) showed a protective effect on stroke patients without drinking (odds ratio 0.82, 95% CI: 0.741–0.908, p = 0.00033, additive model), and no relationship observed between SNP and stroke in patients with drinking. Conclusions: Our results indicate that, in the Chinese population, the ALDH2 variant rs671 is a risk factor of myocardial infarction but a protective factor of stroke without alcohol consumption. The role and pathway of ALDH2 involving in these diseases need more researches.