Biomarkers for ischaemic stroke

Background: Current diagnostic, prognostic and risk stratification tools are inadequate for effective ischaemic stroke management. Hypothesising that –omics approaches can be used to detect novel candidate biomarkers for ischaemic stroke, this thesis aimed to evaluate the current status of biomarkers for ischaemic stroke and develop strategies for biomarker discovery. Methods: Systematic literature review and individual patient data meta-analyses were performed to assess current candidate biomarkers associated with ischaemic stroke. Proteomic SELDI-TOF MS profiling was undertaken to identify novel blood-based protein biomarkers for the diagnosis of acute ischaemic stroke, consisting of a pilot study and a subsequent well-powered discovery study of 104 patients. In an integrative genomics study, transcriptomics data from carotid endarterectomy samples was combined with a genome-wide association study meta-analysis and subjected to functional enrichment analysis to detect differential gene expression or alternative splicing profiles that may be under the control of a genetic variant. Results: Systematic review and meta-analysis concluded that no current candidate biomarkers could be recommended for routine clinical practice, supporting the pursuit of novel biomarkers for ischaemic stroke and informing the design of subsequent experimental studies. SELDI-TOF MS detected two plasma protein ions, m/z 3699 and m/z 6640, which could differentiate between acute cerebral ischaemia and stroke mimics. Protein ion m/z 6640, identified as ApoC 1, highlighted the role of lipid dysregulation and was postulated to be a novel candidate biomarker for acute cerebral ischaemia. Integrative genomics provided evidence for the genetic regulation of cytoskeletal organisation and extracellular matrix remodelling processes in carotid disease. The LTBP4 gene was found to be a candidate risk biomarker for ischaemic stroke by predicting plaque instability and rupture. Conclusions: This work provides workflows for successful biomarker discovery using innovative –omics approaches, highlights key pathogenic pathways and identifies novel candidate biomarkers for ischaemic stroke diagnosis and risk stratification.Open Acces

Keeping a finger on the pulse: Cardiovascular disease rate as a measure of sustainable development

Non-communicable diseases have been somewhat neglected as a public health issue in the past, but there is now growing international consensus that they present a significant obstacle to economic development for both high- and low-income countries. Cardiovascular disease accounts for more than half of all non-communicable disease deaths, and presents a promising target for curbing the non-communicable disease epidemic. This article explains the pressing need for non-communicable disease prevention, focusing on strategies that can be employed to decrease cardiovascular disease risk at an individual and population level, and outlines the UK’s approaches to cardiovascular disease prevention in particular. Given the mounting burden of non-communicable diseases, responsible health governance and a balanced economic policy could consider the use of low cardiovascular disease rates as a measure of positive and sustainable economic development

Efficacy of information interventions in reducing transfer anxiety from a critical care setting to a general ward: A systematic review and meta-analysis

Purpose: Our aim was to undertake a comprehensive systematic review on the efficacy of information interventions on reducing anxiety in patients and family members on transfer from a critical care setting to a general ward. Materials and methods: MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, and Google Scholar databases from 1990 to January 1, 2011, were searched. Bibliographies of identified articles were reviewed. Only high-quality randomized controlled trials comparing an intervention to reduce transfer anxiety with standard care, where transfer anxiety is measured by the validated State Trait Anxiety Inventory, were included. Data were extracted to estimate standard mean differences (SMDs), pooled odds ratios (ORs), and 95% confidence intervals (CIs) using both fixed and random effects model. Results: Of 266 studies identified in the primary search, 5 studies enrolling 629 participants met the inclusion criteria, family members' transfer anxiety was significantly reduced in the intervention arm of information provision (OR, 1.70; 95% CI, 1.15-2.52; P = .01) compared with those who received standard care (OR, 0.42; 95% CI; 0.276-0.625; P < .001), and patients' transfer anxiety was significantly reduced in one study. Conclusions: Providing information to understand a future ward environment can significantly reduce patients' and family members' transfer anxiety from the critical care setting when compared with standard care

Mendelian Randomization to compare estimated risk with observed risk for gene polymorphisms associated with ischemic stroke.

<p>The mean difference (ΔX) was calculated from a meta-analysis relating MTHFR C677T genotype with homocysteine variation in healthy South Asians. The expected OR was calculated using the following formula: <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057305#pone.0057305-Casas1" target="_blank">[16]</a> where 1.68 was the OR associated with 2.90 µmol/L mean difference in homocysteine levels between stroke cases and controls.</p

Candidate-gene analysis of white matter hyperintensities on neuroimaging

Background: White matter hyperintensities (WMH) are a common radiographic finding and may be a useful endophenotype for small vessel diseases. Given high heritability of WMH, we hypothesised that certain genotypes may predispose individuals to these lesions and consequently, to an increased risk of stroke, dementia and death. We performed a meta-analysis of studies investigating candidate genes and WMH to elucidate the genetic susceptibility to WMH and tested associated variants in a new independent WMH cohort. We assessed a causal relationship of WMH to methylene tetrahydrofolate reductase (MTHFR). Methods: Database searches through March 2014 were undertaken and studies investigating candidate genes in WMH were assessed. Associated variants were tested in a new independent ischaemic cohort of 1202 WMH patients. Mendelian randomization was undertaken to assess a causal relationship between WMH and MTHFR. Results: We identified 43 case-control studies interrogating eight polymorphisms in seven genes covering 6,314 WMH cases and 15,461 controls. Fixedeffects meta-analysis found that the C-allele containing genotypes of the aldosterone synthase CYP11B2 T(-344)C gene polymorphism were associated with a decreased risk of WMH (OR=0.61; 95% CI, 0.44 to 0.84; p=0.003). Using mendelian randomisation the association among MTHFR C677T, homocysteine levels and WMH, approached, but did not reach, significance (expected OR=1.75; 95% CI, 0.90-3.41; observed OR=1.68; 95% CI, 0.97-2.94). Neither CYP11B2 T(-344)C nor MTHFR C677T were significantly associated when tested in a new independent cohort of 1202 patients with WMH. Conclusions: There is a genetic basis to WMH but anonymous genome wide and exome studies are more likely to provide novel loci of interest

Meta-analysis, forest plot and pooled ORs of risk from studies investigating MTHFR C677T polymorphism (TT vs CC) -stroke, homocysteine-stroke and homocysteine-MTHFR C677T.

<p>Meta-analysis, forest plot and pooled ORs of risk from studies investigating MTHFR C677T polymorphism (TT vs CC) -stroke, homocysteine-stroke and homocysteine-MTHFR C677T.</p

PRISMA statement flow diagram illustrating search strategy and studies included in the meta-analysis.

<p>*Articles excluded because they did not meet inclusion criteria and were missing genotype data.</p

Effect of genetic variants associated with plasma homocysteine levels on stroke risk

Background and Purpose: Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes. Methods: Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs. Results: One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes. Conclusions: This study found several potential associations with IS and its subtypes: An association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS

Effect of genetic variants associated with plasma homocysteine levels on stroke risk

BACKGROUND AND PURPOSE - : Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes. METHODS - : Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs. RESULTS - : One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel di