29 research outputs found
Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies
No full text<p>Background - Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.</p>
<p>Methods - We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.</p>
<p>Findings - We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10−16) and ZFHX3 (p=2·28×10−8), and for large-vessel stroke at a 9p21 locus (p=3·32×10−5) and HDAC9 (p=2·03×10−12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10−6. However, we were unable to replicate any of these novel associations in the replication cohort.</p>
<p>Interpretation - Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.</p>
GISCOME - Genetics of Ischaemic Stroke Functional Outcome network : A protocol for an international multicentre genetic association study
No full textIntroduction: Genome-wide association studies have identified several novel genetic loci associated with stroke risk, but how genetic factors influence stroke outcome is less studied. The Genetics of Ischaemic Stroke Functional outcome network aims at performing genetic studies of stroke outcome. We here describe the study protocol and methods basis of Genetics of Ischaemic Stroke Functional outcome. Methods: The Genetics of Ischaemic Stroke Functional outcome network has assembled patients from 12 ischaemic stroke projects with genome-wide genotypic and outcome data from the International Stroke Genetics Consortium and the National Institute of Neurological Diseases Stroke Genetics Network initiatives. We have assessed the availability of baseline variables, outcome metrics and time-points for collection of outcome data. Results: We have collected 8831 ischaemic stroke cases with genotypic and outcome data. Modified Rankin score was the outcome metric most readily available. We detected heterogeneity between cohorts for age and initial stroke severity (according to the NIH Stroke Scale), and will take this into account in analyses. We intend to conduct a first phase genome-wide association outcome study on ischaemic stroke cases with data on initial stroke severity and modified Rankin score within 60-190 days. To date, we have assembled 5762 such cases and are currently seeking additional cases meeting these criteria for second phase analyses. Conclusion: Genetics of Ischaemic Stroke Functional outcome is a unique collection of ischaemic stroke cases with detailed genetic and outcome data providing an opportunity for discovery of genetic loci influencing functional outcome. Genetics of Ischaemic Stroke Functional outcome will serve as an exploratory study where the results as well as the methodological observations will provide a basis for future studies on functional outcome. Genetics of Ischaemic Stroke Functional outcome can also be used for candidate gene replication or assessing stroke outcome non-genetic association hypotheses.Peer reviewe
Common variants at 6p21.1 are associated with large artery atherosclerotic stroke
No full textGenome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10 -8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10 -4; discovery and replication combined OR = 1.21, P = 4.7 × 10 -8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke
Data from: Genome-wide association meta-analysis of functional outcome after ischemic stroke
No full textObjective: To discover common genetic variants associated with post-stroke outcomes using a genome-wide association (GWA) study.
Methods: The study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, USA and Australia included in the Genetics of Ischaemic Stroke Functional Outcome (GISCOME) network. The primary outcome was modified Rankin Scale (mRS) score after 60-190 days, evaluated as two dichotomous variables (0-2 versus 3-6 and 0-1 versus 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was P<5×10-8.
Results: We identified one genetic variant associated with functional outcome with genome-wide significance (mRS 0-2 vs 3-6, P=6.8×10-9). This intronic variant (rs1842681) in the LOC105372028 gene, is a previously reported trans-eQTL for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1 (PP1). This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants discovered in this study demonstrated suggestive association with outcome (P<10-5), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g. NTN4, TEK and PTCH1).
Conclusions: In this large GWA study on functional outcome after ischemic stroke we report one significant variant and several variants with suggestive association to outcome three months after stroke onset with plausible mechanistic links to post-stroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted
Lumbar drainage following aneurysmal subarachnoid haemorrhage and the role of cytokine and adhesion molecules in the pathogenesis of delayed ischaemic neurological deficit
No full textIntroduction
Delayed ischaemic neurological deficit (DIND) following aneurysmal subarachnoid haemorrhage (aSAH) is a significant cause of morbidity and mortality. There is some evidence to suggest that its pathogenesis is related to inflammation and that clearing the subarachnoid space of potential
pathogens via a lumbar drain may reduce the prevalence and severity of DIND.
Aims
The aims of the current study are two-fold:
1. To ascertain whether lumbar drainage of cerebrospinal fluid (CSF) following aSAH can reduce the prevalence and severity of DIND.
2. To investigate levels of inflammatory mediators in plasma and CSF and to look for an association with aSAH, DIND and outcome.
Material and methods
1. Prospective randomised controlled trial with randomisation into two arms:
arm 1 control, no additional intervention; Arm 2 study, insertion of a lumbar
drain in order to clear the visible blood load.
2. Prospective cohort study of patients with aSAH. Plasma and CSF samples were obtained on days 3, 5, 7 and 9 following haemorrhage and analysed for 11 mediators.
Results
1. Prevalence of DIND 35% (confidence interval (CI) 26.2-45.2%) in the
control versus 21% (CI 13.6-30.0%) in the study group (p=0.021). A
significant improvement in early clinical outcome in favour of lumbar drainage
was noted (Modified Rankin Score 0-2 37.5% in the control versus 55.2% in
the study group, p=0.009). There was no difference in outcome at six
months.
2. Raised plasma and CSF levels of most mediators when compared with non-aSAH controls. Significantly higher levels of vascular endothelial growth factor within the CSF of patients with DIND on day 5 post ictus when
compared to patients without DIND. Generally higher mediator levels were noted within the CSF when compared to plasma.
Conclusion
This provides some support for the routine use of lumbar drains following aSAH in good grade patients to reduce the prevalence of DIND and improve early clinical outcome. Both a central nervous system and systemic inflammatory response is initiated following aSAH. The former may be associated with DIND. Causality cannot be determined from this study
The Longitudinal Effect of Impaired Kidney Function on Bone Mineral Density and the Association of Body Composition on Biomarkers of Kidney Function Among Afro-Caribbean Men of West African Ancestry
No full textBackground: Chronic kidney disease (CKD) is a rising global health problem. African Americans bear a greater proportion of CKD burden compared to Caucasians. Little is known about the relationship of CKD with bone loss and body composition distribution with biomarkers of CKD in blacks.
Objective: The prevalence of CKD among Tobago black, African American and Caucasian men, aged 40 years and older were determined and compared. The risk factors of CKD, the association of body composition with biomarkers of CKD and the effect of CKD on longitudinal bone loss were examined among Tobago black males.
Methods: Tobago men were recruited from Tobago Island in 2004-2007. Counterparts from U.S were obtained from the National Health and Nutrition Examination Survey (NHANES) 2003-2006. Standardized serum creatinine, cystatin C and urinary albumin were measured using Jaffè reaction, Dade Behring nephelometer and fluorescent immunoassay respectively. Longitudinal Bone Mineral Density changes in trochanter, femoral neck and total hip from 2004/2007-2012 were measured using Dual X-Ray Absorptiomertry (DXA). Body composition was measured using DXA and Peripheral Quantitative Computed Tomography (PQCT). Covariates were assessed from questionnaires in 2004-2007.
Results: The prevalence of CKD was 19.7%, 23.4% and 19.7% in Tobago black, African American and Caucasian men respectively. Age, hypertension and diabetes were significantly associated with CKD in Tobago men. Lean body mass and calf muscle area were positively associated with serum creatinine. All adiposity measures were positively associated with cystatin C, but not with calf muscle area. There was consistent greater decline in BMD across quartiles of ACR, serum creatinine and cystatin C in trochanter, femoral neck and total hip bones. The rate of bone loss in Tobago men was similar to that in Caucasian men.
Public Health Significance: The biomarkers used for assessing CKD (serum creatinine and cystatin C) are influenced by body composition. Future CKD screening among blacks with high lean or muscle mass should include cystatin C assessment due to the influence of muscle mass on serum creatinine.
CKD is associated with bone loss. Proper management of bone minerals and DXA screenings are necessary in order to reduce bone loss among individuals with CKD
Association of Apolipoprotein e with Intracerebral Hemorrhage Risk by Race/Ethnicity: A Meta-analysis
No full textImportance: Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. Objective: To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ϵ4 alleles, the most potent genetic risk factor for ICH. Design, Setting, and Participants: This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. Main Outcomes and Measures: Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. Results: In total, 13124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ϵ2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80;
DNA methylation patterns in cord blood DNA and body size in childhood.
No full textThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.BACKGROUND: Epigenetic markings acquired in early life may have phenotypic consequences later in development through their role in transcriptional regulation with relevance to the developmental origins of diseases including obesity. The goal of this study was to investigate whether DNA methylation levels at birth are associated with body size later in childhood. PRINCIPAL FINDINGS: A study design involving two birth cohorts was used to conduct transcription profiling followed by DNA methylation analysis in peripheral blood. Gene expression analysis was undertaken in 24 individuals whose biological samples and clinical data were collected at a mean ± standard deviation (SD) age of 12.35 (0.95) years, the upper and lower tertiles of body mass index (BMI) were compared with a mean (SD) BMI difference of 9.86 (2.37) kg/m(2). This generated a panel of differentially expressed genes for DNA methylation analysis which was then undertaken in cord blood DNA in 178 individuals with body composition data prospectively collected at a mean (SD) age of 9.83 (0.23) years. Twenty-nine differentially expressed genes (>1.2-fold and p<10(-4)) were analysed to determine DNA methylation levels at 1-3 sites per gene. Five genes were unmethylated and DNA methylation in the remaining 24 genes was analysed using linear regression with bootstrapping. Methylation in 9 of the 24 (37.5%) genes studied was associated with at least one index of body composition (BMI, fat mass, lean mass, height) at age 9 years, although only one of these associations remained after correction for multiple testing (ALPL with height, p(Corrected) = 0.017). CONCLUSIONS: DNA methylation patterns in cord blood show some association with altered gene expression, body size and composition in childhood. The observed relationship is correlative and despite suggestion of a mechanistic epigenetic link between in utero life and later phenotype, further investigation is required to establish causality
Current evidence for a modulation of low back pain by human genetic variants
No full textThe manifestation of chronic back pain depends on structural, psychosocial, occupational and genetic influences. Heritability estimates for back pain range from 30% to 45%. Genetic influences are caused by genes affecting intervertebral disc degeneration or the immune response and genes involved in pain perception, signalling and psychological processing. This inter-individual variability which is partly due to genetic differences would require an individualized pain management to prevent the transition from acute to chronic back pain or improve the outcome. The genetic profile may help to define patients at high risk for chronic pain. We summarize genetic factors that (i) impact on intervertebral disc stability, namely Collagen IX, COL9A3, COL11A1, COL11A2, COL1A1, aggrecan (AGAN), cartilage intermediate layer protein, vitamin D receptor, metalloproteinsase-3 (MMP3), MMP9, and thrombospondin-2, (ii) modify inflammation, namely interleukin-1 (IL-1) locus genes and IL-6 and (iii) and pain signalling namely guanine triphosphate (GTP) cyclohydrolase 1, catechol-O-methyltransferase, μ opioid receptor (OPMR1), melanocortin 1 receptor (MC1R), transient receptor potential channel A1 and fatty acid amide hydrolase and analgesic drug metabolism (cytochrome P450 [CYP]2D6, CYP2C9)
Translational research in rheumatoid arthritis: Exploiting melanocortin receptors
No full textThe copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the authorRheumatoid arthritis (RA) is a chronic inflammatory disease affecting 1% of the population. The aetiology of rheumatoid arthritis is unknown, although there are multiple postulated theories. In 1950, Philip Hench won the Nobel prize for treating patients with rheumatoid arthritis with cortisone. He also treated 6 patients with adrenocorticotropic hormone (ACTH) with good results. ACTH is a melanocortin. The melanocortin system describes the five melanocortin receptors, their ligands, agonists and antagonists and the accessory proteins. The aim of this study was to explore the melanocortin receptors in rheumatoid arthritis synovium.
Methods
HA-tagged stable cell lines were created for MC1R, MC3R and MC5R. Multiple antibodies were tested for their utility using Western Blot, immunohistochemistry and flow cytometry. Samples of synovium from 28 patients with RA were tested using RTPCR for the presence of MC1R and MC3R. Gene expression was correlated with clinical characteristics, cytokine (RTPCR) expression and immunohistochemical score.
Results
The stable cell lines expressed MC1R, MC3R and MC5R respectively. Of the antibodies tested none were found to be of utility in detecting MC1R or MC3R .The MC1R RQ values in rheumatoid synovium appear to split into two groups, high and low. The medians of the two groups are significantly different (p=0.0005). There is almost a 5 cycle, or 64 fold, difference in gene expression between the medians of the two groups (1.59 v 6.23). Of note no MC3R positive samples were CD138 high (i.e. no MC3R positive samples had a significant plasma cell infiltrate) (p=0.006). Categorical analysis using Fishers Exact test revealed an association between MC1R high samples and CD68 lining high scores, (i.e. MC1R high samples also had a high macrophage score in the lining of the sample) (p=0.02). MC1R low samples were associated with not being on combination therapy,
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this did not quite reach significance (p=0.07). Linear regression analysis confirmed these associations for MC1R. PCA analysis did not show any grouping of samples according to any of the variables tested, likely due to sample size.
Conclusion
MC1R and MC3R are found in human synovium. Current commercial antibodies are not of utility in detecting MC1R or MC3R. Synovial samples can be split into high and low MC1R gene expression groups. MC3R was either present or absent. High expression of MC1R was associated with a high macrophage score and MC3R expression was associated with a low plasma cell score. MC1R and MC3R expression in RA synovium could be used as biomarkers of disease state or severity as well as a target for therapy
