| 1. |
- Pulit, SL, et al.
(författare)
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Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.
- 2016
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Ingår i: The Lancet. Neurology. - 1474-4465. ; 15:2, s. 174-84
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16851 cases with state-of-the-art phenotyping data and 32473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20941 cases and 364736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50×10(-8); joint OR 1·19, 1·12-1·26, p=1·30×10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26×10(-19); joint OR 1·37, 1·30-1·45, p=2·79×10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93×10(-7); joint OR 1·17, 1·11-1·23, p=2·29×10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50×10(-8); joint OR 1·24, 1·15-1·33, p=4·52×10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82×10(-8); joint OR 1·17, 1·11-1·23, p=2·92×10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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| 3. |
- Appleton, Jason Philip, et al.
(författare)
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Improving the likelihood of neurology patients being examined using patient feedback
- 2015
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Ingår i: BMJ Quality Improvement Reports. - : BMJ. - 2050-1315. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to establish whether recall of elements of the neurological examination can be improved by use of a simple patient assessment score. In a previous study we demonstrated that in-patients referred to neurology at two United Kingdom (UK) hospitals were not fully examined prior to referral; we therefore designed a larger quality improvement report with 80% power to detect a 10% increase in tendon hammer or ophthalmoscope use following an educational intervention. In-patients referred to neurology over a four month period (in hospitals in the UK (10), Jordan (1), Sweden (2), and the United Arab Emirates (1)) were asked whether they recalled being examined with a tendon hammer (T), ophthalmoscope (O), and stethoscope (S) since admission. The results were disseminated to local medical teams using various techniques (including Grand Round presentations, email, posters, discounted equipment). Data were then collected for a further four month period post-intervention. Pre-intervention and post-intervention data were available for 11 centres with 407 & 391 patients in each arm respectively. Median age of patients was 51 (range 13-100) and 49 (range 16-95) years respectively, with 44.72% and 44.76% being male in each group. 264 patients (64.86%) recalled being examined with a tendon hammer in the pre-intervention arm, which significantly improved to 298 (76.21%) (p<0.001). Only 119 patients (29.24%) recollected examination with an ophthalmoscope pre-intervention, which significantly improved to 149 (38.11%)(p=0.009). The majority of patients (321 (78.87%)) pre-intervention recalled examination with a stethoscope, which significantly improved to 330 (84.4%) to a lesser extent (p=0.045). Results indicate that most patients are not fully examined prior to neurology referral yet a simple assessment score and educational intervention can improve recall of elements of the neurological examination and thus the likelihood of patients being examined neurologically. This is the largest and - to our knowledge - only study to assess this issue. This has implications for national neurological educators.
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| 4. |
- Malik, Rainer, et al.
(författare)
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Low-frequency and common genetic variation in ischemic stroke : The METASTROKE collaboration
- 2016
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Ingår i: Neurology. - 1526-632X. ; 86:13, s. 26-1217
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes.METHODS: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes.RESULTS: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5).CONCLUSIONS: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.
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