Shubham Misra

High-dose statin therapy and risk of intracerebral hemorrhage: a meta-analysis

Statin plays a major role in the primary and secondary prevention of cardiovascular disease (CVD). Inconsistent findings in the studies have been observed toward the risk of intracerebral hemorrhage (ICH) using higher dose of statin. To examine this issue, we performed a meta‐analysis of randomized controlled trials (RCTs) to assess the association between higher dose of various statins and risk of ICH among patients with CVD. Literature was searched for studies published before June 10, 2015, using electronic database ‘PubMed’, ‘EMBASE’, and ‘Google Scholar’ as well as from many trial databases. The following search terms were used: ‘Statin therapy’ AND ‘Cardiovascular Disease’, AND ‘Dose’ AND ‘Intracerebral hemorrhage’, AND ‘Randomized Controlled Trials’ AND ‘High Dose Statin’. High dose of statins was defined as atorvastatin 80 mg, simvastatin 80 mg, pravastatin 40 mg, rosuvastatin 20 mg per day. Fixed‐effect model was used to estimate the risk ratio (RR) and 95% confidence interval (CI) if heterogeneity was <50%; otherwise, random‐effect model was used. Beggs funnel plot was used to assess the publication bias. Seven RCTs involving 31,099 subjects receiving high‐dose statin and 31,105 subjects receiving placebo were analyzed in our meta‐analysis. A significant risk of ICH was observed in subjects with higher dose of statin (RR = 1.53; 95% CI: 1.16–2.01; P = 0.002). There was no difference in all‐cause mortality between the two groups (RR = 0.95; 95% CI: 0.86–1.06; P = 0.36). No publication bias was observed through Beggs funnel plot. Higher dose of statins was found to be associated with the risk of ICH. Future studies are needed to confirm these findings.

Association between Interleukin-10 -1082G/A Gene Polymorphism and Risk of Stroke in the North Indian Population: A Case-Control Study.

BACKGROUND Anti-inflammatory interleukin-10 (IL-10) cytokine and its genetic variations may play an important role in the pathogenesis of various human diseases including stroke. OBJECTIVE The aim of this present case-control study was to determine the association between IL-10 -1082G/A (rs1800896) gene polymorphism and risk of stroke in the North Indian population. METHODS Genotyping was carried out by using SNaPshot method (Applied Biosystems, Foster City, California, United States) for 250 ischemic stroke (IS) patients, 250 age- and sex-matched IS free controls, 100 intracerebral hemorrhage (ICH) patients, and 100 age- and sex-matched ICH free controls. IS was classified using the Trial of Org 10172 in Acute Stroke Treatment classification. Conditional logistic regression analysis with adjustment for multiple demographic and risk factor variables was used to calculate the strength of association between IL-10 (-1082G/A) polymorphism and risk of stroke. RESULTS Conditional logistic regression analysis showed an independent association between IL-10 -1082G/A and risk of IS under a dominant model (odds ratio [OR] = 2.39, 95% confidence interval [CI] = 1.34-4.27, P = .003) and an allelic model (OR = 2.49, 95% CI 1.71-3.63, P < .001). An independent association between IL-10 -1082G/A, under the dominant model (OR = 6.8, 95% CI 2.2-20.7, P < .001) and the allelic model (OR = 3.4, 95% CI 1.8-6.3, P < .001), and the risk of ICH was also observed. CONCLUSION Our results suggest that IL-10 -1082G/A gene polymorphism is an independent risk factor for the risk of IS and ICH in the North Indian population. Our findings indicate that IL-10 -1082G/A polymorphism may be used as a genetic marker for identifying individuals at increased risk of developing stroke.

Genetic association between inflammatory genes (IL-1α, CD14, LGALS2, PSMA6) and risk of ischemic stroke: A meta-analysis

Background Sequence variations in genes involved in inflammatory system are known to contribute to the risk of cerebrovascular diseases (CVD) including stroke. Very few number of studies have been published in the context of the association between Interleukin-1α(IL-1α), CD14 cell surface glycoprotein (CD14), Galectin-2-encoding gene (LGALS2)and proteasome subunit type 6 (PSMA6) gene polymorphisms with susceptibility to ischemic stroke (IS). Objective The present meta-analysis aimed to provide a comprehensive account of the association between IL-1α (-C889T and -C511T), CD14 (-C159T), LGALS2 (-C3279T) and PSMA6 (-C8G) gene polymorphisms and susceptibility to IS. Methods A literature search for eligible genetic studies published before August 31, 2015 was conducted in the PubMed, Medline, EMBASE, OVID, and Google Scholar databases. Fixed or random effects models were used to estimate the Pooled Odds ratio (OR) and 95% confidence interval (CI) using RevMan 5.3 software. Results Total 21 studies were included in our meta-analysis. No significant association was observed between IL-1α (-C889T) [OR = 1.18, 95% CI: 0.67–2.08, P = 0.58], IL-1α (-C511T) [OR = 0.95, 95% CI: 0.66–1.37, P = 0.77], LGALS2(-C2379T) [OR = 0.29, 95% CI: 0.02–4.26, P = 0.37] and CD14 (-C260T) [OR = 0.93, 95% CI: 0.77–1.11, P = 0. 42] gene polymorphisms and risk of IS. However, protective level of association was observed between PSMA6 (-C8G) gene polymorphism and susceptibility to IS under the recessive model [OR = 0.25, 95% CI: 0.08–0.72, P = 0.01]. Conclusion Our meta-analysis shows that IL-1α (-C889T and -C511T), CD14 (-C159T), LGALS2 (-C3279T) and gene polymorphisms are not significantly associated with the risk of IS while PSMA6 (-C8G) gene polymorphism may play a protective role with the susceptibility of IS. Further prospective large epidemiological studies are needed to confirm these findings in different populations.

Role of Interleukin-10 (-1082A/G) gene polymorphism with the risk of ischemic stroke: a meta-analysis.

The role of anti-inflammatory Interleukin-10 (IL-10) cytokine gene polymorphism with the risk of ischemic stroke (IS) remains controversial. The aim of present meta-analysis was to investigate the association of IL-10 (-1082 A/G) gene polymorphism with the risk of IS. A literature search for candidate gene association studies published before 29 February 2016 was conducted in the PubMed, EMBASE, Google Scholar, and TRIP database. The following search terms were used: ‘Interleukin-10’ or ‘IL-10’ and ‘Ischemic stroke’ or ‘IS’ and ‘Cerebral Infarction’ or ‘CI’ and ‘genetic polymorphism’ or ‘single nucleotide polymorphisms’ or ‘SNP’. Fixed or random effects models were used to estimate the pooled odds ratios (ORs) and 95% confidence intervals (CIs). Begg’s funnel plot was used to assess the potential for publication bias. In our meta-analysis, five case-control studies involving 1209 IS cases and 1139 controls were included. Overall, there was no significant association between IL-10 (-1082 A/G) [rs1800896] and risk of IS under dominant [AA + AG vs. GG], recessive [AA vs. AG + GG], and allelic [G vs.A] models. However, based on Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, we observed significant association of IL-10 (-1082 A/G) gene polymorphism with the risk of IS for Large Vessel Disease (LVD), Small Vessel Disease (SVD), and other (others due to determined and undetermined etiology) subtypes of IS. This is the first meta-analysis to conclude that IL-10-1082A/G gene polymorphism is associated with the risk of LVD, SVD, and other subtypes of IS. Further well-designed large sample size studies based on TOAST classification are needed to validate these findings.

Tumor necrosis factor-alpha (- 308G/A, + 488G/A, - 857C/T and -1031 T/C) gene polymorphisms and risk of ischemic stroke in north Indian population: A hospital based case-control study.

Background Genetic factors may play a role in the susceptibility of Ischemic stroke (IS). Previous studies have shown that Tumour necrosis factor-α (TNF-α) gene polymorphisms were associated with the risk of IS in multiple ethnicities. The present case–control study tested the hypothesis that genetic polymorphisms of the TNF-α gene may affect the risk of IS in North Indian population. We investigated the association of four single nucleotide polymorphisms (− 308G/A, + 488G/A, − 857C/T and -1031 T/C) within TNF-α gene promoter and their haplotypes with the risk of IS. Methods IS was classified using the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) classification. Genotyping was performed for 250 IS patients and 250 age- and sex-matched IS free controls by using SNaPshot technique. Multivariate logistic regression was used to control the confounding effects of demographic and risk factor variables. Haplotype analyses were done by using PHASE software and Linkage disequilibrium (LD) analyses were done by using Haploview version 4.2 software. Results An independent association between TNF-α + 488G/A (OR = 2.59; 95%CI 1.46 to 4.60; p = 0.001) and -857C/T (OR = 1.77; 95%CI 1.01 to 3.11; p < 0.04) and risk of IS was observed under dominant model. However, no significant association between -308G/A and -1031 T/C gene polymorphisms and risk of IS was observed. Haplotype analysis showed that A308-G488-C857-T1031 haplotypes were significantly associated with the increased risk of IS [OR = 1.66; 95%CI 1.02 to 2.71; p = 0.003]. Strong linkage disequilibrium (LD) was observed for + 488G/A and -857C/T (D’ = 0.41, r2 = 0.004). Conclusions Two SNPs (+ 488G/A and -857C/T) of TNF-α gene and their haplotypes are significantly associated with the risk of IS in the population enrolled from North India. Our findings indicate that polymorphisms and haplotypes of TNF-α gene may be used as a genetic marker for identifying individuals at increased risk for developing IS.

Association between Endothelial nitric oxide synthase G894T gene polymorphism and risk of ischemic stroke in North Indian population: a case-control study.

Background and purpose: Stroke is a multi-factorial disease influenced by both genetic and environmental factors. The aim of this case-control study was to determine the association between Endothelial Nitric Oxide Synthase G894T (rs1799983) gene polymorphism and susceptibility to ischemic stroke (IS) in North Indian population. Methods: In this present case-control study, genotyping was performed by using Polymerase chain reaction – Restriction fragment length polymorphism (PCR-RFLP) method for 250 IS patients and 250 age and sex matched controls. PCR results were confirmed by DNA sequencing. Frequency distribution of genotypes and alleles were compared between cases and controls using conditional logistic regression. Results: Hypertension, Diabetes, Dyslipidemia, Low Socioeconomic Status and Family History of Stroke were found to be independent risk factors for IS. Mean age of cases and controls were 52.83 ± 12.59 and 50.97 ± 12.70 years. Multivariate logistic regression analysis showed a significant association between eNOS G894T (rs1799983) polymorphism and risk of IS [OR = 1.57; 95%CI 1.05–2.37; p = 0.028] under dominant model. Based on Trial of Org 10172 in Acute Stroke Treatment classification, an independent association of large vessel disease (LVD) was observed with the risk of IS under the dominant [OR = 2.09; 95% CI 1.17–3.75; p = 0.01] and recessive [4.09 95% CI 1.06–15.68; p = 0.04] models. All the observed genotype frequencies were in accordance with the Hardy–Weinberg equilibrium (HWE) in both cases and controls. Conclusion: The findings of the present study suggest that polymorphism in G894T position of eNOS gene might be a risk factor for IS mainly for LVD stroke subtype in North Indian population. Further large prospective studies are required to confirm these findings.

Biomarkers to enhance accuracy and precision of prediction of short-term and long-term outcome after spontaneous intracerebral haemorrhage: a study protocol for a prospective cohort study

BackgroundSeveral studies reported prognostic value of biomarker in intracerebral hemorrhagic (ICH) but they are either preliminary observation or inadequately powered to analyse independent contribution of biomarkers over and above clinical and neuroimaging data.ObjectiveTo examine whether the biomarker can significantly add to the predictive accuracy of prognosis of ICH.Method/designIn a multi-centric prospective cohort study, 1020 patients with ICH within 72 hours of onset are being recruited. After obtaining written informed consent from patients/proxy, venous blood sample (10 ml) is being collected and analysed for C-reactive protein (CRP) level, S100B, Glial fibrillary acidic protein (GFAP), Troponin, change in leukocyte count and Copeptin levels. The patients are telephonically followed using stroke scales (Barthel Index and modified Rankin Scale) at 3, 6, 12 months and 2 years after the recruitment.DiscussionThis protocol will aim at predicting the short term or long term prognosis with the use of clinical, neuroimaging and biomarkers in order to help clinician to stratify patients for early referral or intervention.

Association of Transforming Growth Factor Beta-1-509C/T Gene Polymorphism with Ischemic Stroke: A Meta Analysis

Introduction: Transforming Growth Factor-Beta 1 (TGF-β1) is a pleiotropic cytokine with potent anti-inflammatory property, which has been considered as an essential risk factor in the inflammatory process of Ischemic Stroke (IS), by involving in the pathophysiological progression of hypertension, atherosclerosis, and lipid metabolisms. -509C/T TGF-β1 gene polymorphism has been found to be associated with the risk of IS. The aim of this meta-analysis was to provide a relatively comprehensive account of the relation between -509C/T gene polymorphisms of TGF-β1 and susceptibility to IS. Methods: A review of literature for eligible genetic association Studies published before October 20, 2014 was conducted in the PubMed, EMBASE, Google Scholar and Trip database. The strength of association was calculated by pooled odds ratios (ORs) with 95% confidence intervals using RevMan 5.3 software. Heterogeneity was examined using Higgins I-squared, Tau-squared, and Chi-squared tests. Results: A total of 2 studies involving 614 cases and 617 controls were found. The overall estimates did not show any significant relation between TGF-β1-509C/T polymorphism and risk of IS under dominant (CC+CT vs. TT: OR=1.01, 95%CI=0.31 to 3.26; P=0.99), recessive (CC vs. CT+TT: OR=0.94, 95%CI=0.47 to 1.90; P=0.87), and allelic models (T vs. C: OR=1.06, 95%CI=0.55 to 2.04; P=0.86). Conclusion: This meta-analysis showed that TGF-β1-509C/T gene polymorphism has no significant association with the susceptibility of IS. Further well-designed prospective studies with larger sample size are needed to confirm these findings.

Association between Interleukin-6 (-174 G/C and -572 C/G) Promoter Gene Polymorphisms and Risk of Intracerebral Hemorrhage in North Indian Population: A Case Control Study

Background: Interleukin-6 (IL-6), a pro-inflammatory cytokine is involved in various vascular pathologies including stroke. Till date, no studies have been reported for the association between IL-6 gene polymorphisms with the risk of Intracerebral hemorrhage (ICH). Objective: The aim of this present case-control study was to investigate the association between IL-6 (-174 G/C and -572 C/G) gene polymorphisms and risk of ICH in North Indian population. Methods: Genotyping was carried out by using SNaPshot method for ICH patients and 100 age-sex matched ICH free controls. Conditional logistic regression analysis with adjusting multiple demographic and risk factor variables was used to calculate the strength of association between IL-6 (-174 G/C and -572 C/G) polymorphisms and risk of ICH. Results: Hypertension, diabetes, dyslipidemia, smoking and low socioeconomic status were found to be associated with the risk of ICH. The distribution of -174 G/C and -572 C/G genotypes was consistent with Hardy Weinberg Equilibrium (HWE) in the ICH and control subjects. Conditional logistic regression analysis showed a significant association between IL-6 -572 C/G gene polymorphism and the risk of ICH under dominant model (OR=3.7; 95%CI 1.05 to 13.1; p=0.004) and allelic model (OR=2.6; 95%CI 1.1 to 6.2; p=0.01). No significant association was observed for the association between IL-6 -174 G/C gene polymorphism and risk of ICH. Conclusion: Our results suggest that IL-6 (-572 C/G) polymorphism is significantly associated with the risk of ICH in North Indian population. Further prospective studies with large sample size are needed for independent validation.

Blood based protein biomarkers for stroke differentiation: A systematic review

Computed tomography (CT) scan is the mainstay for diagnosis of stroke; but the facility of CT scan is not easily available. A blood‐based biomarker approach is required to distinguish ischemic stroke (IS) from hemorrhagic stroke (HS) in pre‐hospital settings.To conduct a systematic review of diagnostic utility of blood biomarkers for differential diagnosis of stroke.A comprehensive literature search was carried out till March 7, 2017 in PubMed, Cochrane, Medline, OVID, and Google Scholar databases. Methodological quality of each study was assessed using the modified Quality Assessment of Diagnostic Accuracy Studies questionnaire.Eighteen studies were identified relevant to our systematic review. Ten single biomarkers and seven panels of different biomarkers were identified which showed potential for differentiating IS and HS. Activated Protein C‐ Protein C Inhibitor Complex (APC‐PCI) (sensitivity‐96%), Glial Fibrillary Acidic Protein (GFAP) (specificity‐100%) and a panel of APC‐PCI & GFAP (sensitivity‐ 71%) and Retinol Binding Protein 4 (RBP4) & GFAP (specificity‐ 100%) were found to have high sensitivity and specificity for differentiating the two stroke types.Our systematic review does not recommend the use of any blood biomarker for clinical purposes yet based on the studies conducted till date.