Yi Chen Hsieh

Association between genetic variant on chromosome 12p13 and stroke survival and recurrence: a one year prospective study in Taiwan

BackgroundThe association between ischemic stroke and 2 single nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579 appears inconsistent across different samples. These SNPs are close to the ninjurin2 gene which may alter the risk of stroke by affecting brain response to ischemic injury. The purpose of this study was to investigate the association between these two SNPs and ischemic stroke risk, as well as prognostic outcomes in a Taiwanese sample.MethodsWe examined the relations of these two SNPs to the odds of new-onset ischemic stroke, ischemic stroke subtypes, and to the one year risk of stroke-related death or recurrent stroke following initial stroke in a case-control study. A total of 765 consecutive patients who had first-ever ischemic stroke were compared to 977 stroke-free, age-matched controls. SNPs were genotyped by Taqman fluorescent allelic discrimination assay. The association between ischemic stroke and SNPs were analyzed by multivariate logistic regression. Cox proportional hazard model was used to assess the effect of individual SNPs on stroke-related mortality or recurrent stroke.ResultsThere was no significant association between SNP rs12425791 and rs11833579 and ischemic stroke after multiple testing corrections. However, the marginal significant association was observed between SNP rs12425791 and large artery atherosclerosis under recessive model (OR, 2.30; 95%CI, 1.22-4.34; q-value = 0.062). Among the 765 ischemic stroke patients, 59 died or developed a recurrent stroke. After adjustment for age, sex, vascular risk factors and baseline stroke severity, Cox proportional hazard analysis indicated that the hazard ratios were 2.76 (95%CI, 1.34-5.68; q-value, 0.02) and 2.15 (95%CI, 1.15-4.02; q-value, 0.03) for individuals with homozygous variant allele of rs12425791 and rs11833579, respectively.ConclusionsThis is a precedent study that found genetic variants of rs12425791 and rs11833579 on chromosome 12p13 are independent predictors of stroke-related mortality or stroke recurrence in patients with incident ischemic stroke in Taiwan. Further study is needed to explore the details of the physiological function and the molecular mechanisms underlying the association of this genetic locus with ischemic stroke.

GT-repeat polymorphism in the heme oxygenase-1 gene promoter is associated with cardiovascular mortality risk in an arsenic-exposed population in northeastern Taiwan.

Inorganic arsenic has been associated with increased risk of atherosclerotic vascular disease and mortality in humans. A functional GT-repeat polymorphism in the heme oxygenase-1 (HO-1) gene promoter is inversely correlated with the development of coronary artery disease and restenosis after clinical angioplasty. The relationship of HO-1 genotype with arsenic-associated cardiovascular disease has not been studied. In this study, we evaluated the relationship between the HO-1 GT-repeat polymorphism and cardiovascular mortality in an arsenic-exposed population. A total of 504 study participants were followed up for a median of 10.7 years for occurrence of cardiovascular deaths (coronary heart disease, cerebrovascular disease, and peripheral arterial disease). Cardiovascular risk factors and DNA samples for determination of HO-1 GT repeats were obtained at recruitment. GT repeats variants were grouped into the S (<27 repeats) or L allele (≥ 27 repeats). Relative mortality risk was estimated using Cox regression analysis, adjusted for competing risk of cancer and other causes. For the L/L, L/S, and S/S genotype groups, the crude mortalities for cardiovascular disease were 8.42, 3.10, and 2.85 cases/1000 person-years, respectively. After adjusting for conventional cardiovascular risk factors and competing risk of cancer and other causes, carriers with class S allele (L/S or S/S genotypes) had a significantly reduced risk of cardiovascular mortality compared to non-carriers (L/L genotype) [OR, 0.38; 95% CI, 0.16-0.90]. In contrast, no significant association was observed between HO-1 genotype and cancer mortality or mortality from other causes. Shorter (GT)n repeats in the HO-1 gene promoter may confer protective effects against cardiovascular mortality related to arsenic exposure.

Association of heme oxygenase-1 GT-repeat polymorphism with blood pressure phenotypes and its relevance to future cardiovascular mortality risk: An observation based on arsenic-exposed individuals

OBJECTIVE Heme oxygenase (HO)-1 is up-regulated as a cellular defense responding to stressful stimuli in experimental studies. A GT-repeat length polymorphism in the HO-1 gene promoter was inversely correlated to HO-1 induction. Here, we reported the association of GT-repeat polymorphism with blood pressure (BP) phenotypes, and their interaction on cardiovascular (CV) mortality risk in arsenic-exposed cohorts. METHODS Associations of GT-repeat polymorphism with BP phenotypes were investigated at baseline in a cross-sectional design. Effect of GT-repeat polymorphism on CV mortality was investigated in a longitudinal design stratified by hypertension. GT-repeat variants were grouped by S (<27 repeats) or L (≥ 27 repeats) alleles. Multivariate analyses were used to estimate the effect size after accounting for CV covariates. RESULTS Totally, 894 participants were recruited and analyzed. At baseline, carriers with HO-1 S alleles had lower diastolic BP (L/S genotypes, P = 0.014) and a lower possibility of being hypertensive (L/S genotypes, P = 0.048). After follow-up, HO-1 S allele was significantly associated with a reduced CV risk in hypertensive participants [relative mortality ratio (RMR) 0.27 (CI 0.11, 0.69), P = 0.007] but not in normotensive. Hypertensive participants without carrying the S allele had a 5.23-fold increased risk [RMR 5.23 (CI 1.99, 13.69), P = 0.0008] of CV mortality compared with normotensive carrying the S alleles. CONCLUSIONS HO-1 short GT-repeat polymorphism may play a protective role in BP regulation and CV mortality risk in hypertensive individuals against environmental stressors.

A significant decrease in blood pressure through a family-based nutrition health education programme among community residents in Taiwan

OBJECTIVE To evaluate the effect on decrease in blood pressure of modifying risk factors for stroke, such as blood lipid profiles, diet habits and indices of body weight, through a family-based nutrition health education programme among hypertensive patients and pre-hypertensive subjects without taking any antihypertensive drugs. DESIGN AND SETTING This was a community-based prospective study. The study population was randomly selected from communities in Taipei; potential subjects were invited by telephone to participate. SUBJECTS After excluding subjects whose blood pressure was normal and those using antihypertensive drugs, there were 390 participants included in the study. Subjects in the intervention group (n 293) received nutrition health education on blood pressure control and stroke-related risk factor modification at each visit. Non-intervention subjects (n 97) only acquired a general education sheet available in clinics. The blood pressure of study subjects was measured at baseline and 6-month follow-up to evaluate the interventions effect on decrease in blood pressure. RESULTS Significant decreases of 2.0 mmHg and 5.9 mmHg in systolic blood pressure were observed both in pre-hypertensive and hypertensive subjects in the intervention group. Additionally, intervention subjects with improvement of total cholesterol and LDL cholesterol, decrease in indices of body weight and increase in consumption of fruit and vegetables also had significant lowering of blood pressure. CONCLUSIONS The present study provided evidence that the blood pressure of pre-hypertensive and hypertensive subjects could decrease significantly, without taking antihypertensive drugs, after modifying blood lipid profiles and waist by dietary habits changed through a family-based nutrition heath education programme, resulting in a significant effect on stroke risk reduction.

Association of blood active matrix metalloproteinase-3 with carotid plaque score from a community population in Taiwan

OBJECTIVE Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of atherosclerosis. However, the relationship between blood levels of MMPs and the extent of carotid atherosclerosis remains uncertain. We assessed blood levels of active MMPs in relation to the extent of carotid plaque formation and intima-media thickness (IMT) in a community population in Taiwan. METHODS In 433 subjects from a community primary stroke prevention program, blood levels of active MMP-1, total and active MMP-3 and active MMP-9 were determined using enzyme-linked immunosorbent assays, carotid plaque score (PS) and IMT by high-resolution B-mode ultrasonography and the common MMP-1, MMP-3, and MMP-9 promoter low- and high-activity genotypes by polymerase chain reaction and restriction fragment length polymorphism. RESULTS Study subjects were separated into 3 groups based on PS: group 1 (PS=0), group 2 (PS=1-2) and group 3 (PS≥3). Blood levels of active and total MMP-3 bear a highly significant relationship with PS (both p<0.0001). A multiple ordinal logistic regression analysis revealed that blood levels of active MMP-3 are correlated with PS (OR, 1.4; 95% CI, 1.1-1.8; p=0.0038) but not IMT. MMP-3 -1612 6A6A is a dominant genotype in this population, which is associated with higher levels of blood active MMP-3. CONCLUSION Blood levels of active MMP-3 are associated with the extent of carotid atherosclerosis based on PS but not IMT in this community population in Taiwan and the MMP-3 -1612 6A6A genotype is associated with higher levels of blood active MMP-3.

Association of Estrogen Receptor α Genotypes/ Haplotypes With Carotid Intima-Media Thickness in Taiwanese Women

The estrogen receptor α gene (ESR1) is an important mediator of the atheroprotective effect of estrogen on the vasculature system. We examined the potential associations between common single nucleotide polymorphism (SNP) variants of ESR1 and intima-media thickness (IMT) in carotid arteries, a strong predictor of cardiovascular disease (CVD). A total of 760 study participants (343 men and 407 women), who had undergone a Duplex ultrasonographic examination of carotid artery, were investigated. Measurement of IMT was performed on a 10-mm segment of the common carotid artery (CCA). Fourteen sequence-validated SNPs of high frequency of Oriental origin were selected and genotyped by the method of Light-Cycler-480-assisted real-time polymerase chain reaction (PCR) followed by melting curve analysis. Results from multiple linear regression analyses showed significant associations of SNPs rs2228480 (Ex8+229G>A) and rs3798758 (Ex8+1988C>A) with the carotid IMT values in women but not in men. Women with SNP rs2228480 (Ex8+229G>A) A/A genotype had a 0.048 mm (7.1%) increase in IMT values versus the other genotypes combined (P = .030). In women who carried the rs3798758 (Ex8+1988C>A) CA+AA combined genotypes, their carotid IMT measures were 0.020 mm (2.9%) decreased as compared with those in women who carried C/ C genotype (P = .042). In haplotype analysis, women with the T-A haplotype versus C-C haplotype of combined rs3798577 (Ex8+1264T>C) and rs3798758 (Ex8+1988C>A) were also found to be associated with a decreased IMT value at a borderline significance (P = .057). Some common SNPs in the ESR1 could be important in modulating carotid atherosclerosis and thereby CVD susceptibility in Taiwanese women.

Early Menarche and Ischemic Stroke Risk Among Postmenopausal Women

SUMMARY Background: Results from previous studies regarding relationships between age at menarche and cardiovascular disease remain controversial. This study investigated the association between endogenous estrogen exposure and ischemic stroke risk. Methods: A total of 189 ischemic stroke patients and 192 age-matched healthy postmenopausal women were recruited. Age at menarche and menopause and risk factors of ischemic stroke were recorded through structured questionnaires by well-trained research assistants. Lifetime estrogen exposure was calculated as the number of years between age of menarche and menopause. Results: Study subjects with a history of hypertension and diabetes mellitus have a 2.8- and 6.2-fold increased risk for ischemic stroke, respectively. In addition, study subjects with waist circumferences ≥ 80 cm also have a 2.6-fold increased risk of ischemic stroke. Conversely, subjects who experienced menarche at an early age may have a significantly decreased risk of 0.3-fold for ischemic stroke. Moreover, there was a significant and joint protective effect for study subjects without any risk factors of ischemic stroke, including a history of hypertension and diabetes mellitus, late age at menarche, and shorter lifetime estrogen exposure; these subjects were found to have the lowest risk (0.03-fold) for the development of ischemic stroke. Conclusion: Our study provides strong evidence that a significant joint protective effect was observed for patients who undergo early menarche, have longer estrogen exposure and no history of hypertension or diabetes mellitus on the risk of ischemic stroke. (International Journal of Gerontology 2010; 4(1): 16-22)

Comparison of admission random glucose, fasting glucose, and glycated hemoglobin in predicting the neurological outcome of acute ischemic stroke: a retrospective study

Background Hyperglycemia is a known predictor of negative outcomes in stroke. Several glycemic measures, including admission random glucose, fasting glucose, and glycated hemoglobin (HbA1c), have been associated with bad neurological outcomes in acute ischemic stroke, particularly in nondiabetic patients. However, the predictive power of these glycemic measures is yet to be investigated. Methods This retrospective study enrolled 484 patients with acute ischemic stroke from January 2009 to March 2013, and complete records of initial stroke severity, neurological outcomes at three months, and glycemic measures were evaluated. We examined the predictive power of admission random glucose, fasting glucose, and HbA1c for neurological outcomes in acute ischemic stroke. Furthermore, subgroup analyses of nondiabetic patients and patients with diabetes were performed separately. Results Receiver operating characteristic (ROC) analysis revealed that admission random glucose and fasting glucose were significant predictors of poor neurological outcomes, whereas HbA1c was not (areas under the ROC curve (AUCs): admission random glucose = 0.564, p = 0.026; fasting glucose = 0.598, p = 0.001; HbA1c = 0.510, p = 0.742). Subgroup analyses of nondiabetic patients and those with diabetes revealed that only fasting glucose predicts neurological outcomes in patients with diabetes, and the AUCs of these three glycemic measures did not differ between the two groups. A multivariate logistic regression analysis of the study patients indicated that only age, initial stroke severity, and fasting glucose were independent predictors of poor neurological outcomes, whereas admission random glucose and HbA1c were not (adjusted odds ratio: admission random glucose = 1.002, p = 0.228; fasting glucose = 1.005, p = 0.039; HbA1c = 1.160, p = 0.076). Furthermore, subgroup multivariate logistic regression analyses of nondiabetic patients and those with diabetes indicated that none of the three glycemic measures were associated with poor neurological outcomes. Discussion Fasting glucose is an independent predictor of poor neurological outcomes in patients with acute ischemic stroke and had greater predictive power than that of admission random glucose and HbA1c. The predictive power of glycemic measures for poor neurological outcomes did not differ significantly between the nondiabetic patients and those with diabetes.

Associations of estradiol levels and genetic polymorphisms of inflammatory genes with the risk of ischemic stroke

BackgroundEstrogen plays an important role as an anti-inflammatory and neuroprotective agent in ischemic stroke. In this study, we analyzed the effect of a polygenic risk score (PRS) constructed using inflammatory genes and estradiol levels on the risk of ischemic stroke.MethodsThis case-control study was conducted with 624 ischemic stroke patients and 624 age- and gender-matched controls. The PRS estimated the polygenic contribution of inflammatory genes from ischemic stroke susceptibility loci. Estradiol levels were measured using a radioimmunoassay. High and low estradiol levels were defined according to the log-transformed median estradiol levels in female and male controls.ResultsSubjects in the fourth quartile of the PRS had a significant 1.57-fold risk of ischemic stroke (95% confidence interval [CI], 1.12 ~ 2.19), after adjusting for covariates compared to individuals in the lowest quartile. Compared to individuals with high estradiol levels and a low PRS as the reference group, those exposed to low estradiol levels and a high PRS had an increased risk of ischemic stroke (odds ratio, 3.35; 95% CI, 1.79 ~ 6.28). Similar results were also observed in males when the analysis was stratified by gender.ConclusionsOur data suggest that the PRS can be useful in evaluating a high risk of ischemic stroke among patients, especially those exposed to low estradiol levels.