ORCID Profile
0000-0002-3870-8018
Current Organisation
University of Oxford
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 26-02-2019
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.JACC.2018.09.085
Abstract: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. This study sought to test the association between the rs9349379 genotype and SCAD. Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-01-2019
DOI: 10.1212/WNL.0000000000006851
Abstract: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10 −8 and LINC00539/ZDHHC20, p = 5.82 × 10 −9 . Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up s le or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( p value for BI, p [BI] = 9.38 × 10 −25 p [SSBI] = 5.23 × 10 −14 for hypertension), smoking ( p [BI] = 4.4 × 10 −10 p [SSBI] = 1.2 × 10 −4 ), diabetes ( p [BI] = 1.7 × 10 −8 p [SSBI] = 2.8 × 10 −3 ), previous cardiovascular disease ( p [BI] = 1.0 × 10 −18 p [SSBI] = 2.3 × 10 −7 ), stroke ( p [BI] = 3.9 × 10 −69 p [SSBI] = 3.2 × 10 −24 ), and MRI-defined white matter hyperintensity burden ( p [BI] = 1.43 × 10 −157 p [SSBI] = 3.16 × 10 −106 ), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( p ≤ 0.0022), without indication of directional pleiotropy. In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
Publisher: Springer Science and Business Media LLC
Date: 28-08-2013
DOI: 10.1038/NATURE12508
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-07-2014
Publisher: Springer Science and Business Media LLC
Date: 12-03-2018
Publisher: Public Library of Science (PLoS)
Date: 18-03-2015
Publisher: Public Library of Science (PLoS)
Date: 23-04-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-03-2016
Publisher: Springer Science and Business Media LLC
Date: 08-2016
DOI: 10.1038/NATURE19057
Publisher: Elsevier BV
Date: 11-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2014
DOI: 10.1161/STROKEAHA.113.002707
Abstract: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance ( P .01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 in iduals with the ischemic large artery stroke (LAS) subtype. Common variants associated with CAD at P .01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance ( P ×10 −8 ) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 ( P IS =1.62×10 −7 ) and ABO ( P IS =2.6×10 −4 ), as well as at HDAC9 ( P LAS =2.32×10 −12 ), 9p21 ( P LAS =3.70×10 −6 ), RAI1-PEMT-RASD1 ( P LAS =2.69×10 −5 ), EDNRA ( P LAS =7.29×10 −4 ), and CYP17A1-CNNM2-NT5C2 ( P LAS =4.9×10 −4 ). Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
Publisher: American Medical Association (AMA)
Date: 07-2009
Publisher: Elsevier BV
Date: 03-2012
Publisher: Springer Science and Business Media LLC
Date: 03-12-2018
DOI: 10.1038/S41467-018-07340-5
Abstract: Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 in iduals for cIMT, and 48,434 in iduals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4 . LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.
Publisher: Oxford University Press (OUP)
Date: 26-02-2013
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1186/S12872-019-1187-Z
Abstract: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Published and in idual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57 1.22) for the GS, compared to 0.85 (95% CI 0.78 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11 1.50) for the GS, as compared to 1.00 (95% CI 0.96 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown although precision was moderate.
Publisher: Public Library of Science (PLoS)
Date: 11-2018
Publisher: Massachusetts Medical Society
Date: 21-08-2008
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2015
DOI: 10.1161/STROKEAHA.114.007930
Abstract: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has h ered gene discovery, motivating analyses of diagnostic subtypes with reduced s le sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, in idual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA–SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. High genetic correlation was identified between LAA and SVD using linear mixed models ( r g =0.96, SE=0.47, P =9×10 −4 ) and profile scores ( r g =0.72 95% confidence interval, 0.52–0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association ( P =1×10 −7 ) for single nucleotide polymorphisms near the opioid receptor μ1 ( OPRM1 ) gene. Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.
Publisher: Massachusetts Medical Society
Date: 28-09-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2016
DOI: 10.1161/STROKEAHA.115.011328
Abstract: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset years. The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P ×10 −6 and performed in silico association analyses in an independent s le of ≤1003 cases and 7745 controls. One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all s les from the discovery and follow-up stages (rs11196288 odds ratio =1.41 P =9.5×10 −9 ). The associated locus is in an intergenic region between TCF7L2 and HABP2 . In a further analysis in an independent s le, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII–activating protease levels, a product of HABP2 . HABP2 , which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
Publisher: Springer Science and Business Media LLC
Date: 03-06-2019
DOI: 10.1038/S41588-019-0449-0
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Elsevier BV
Date: 06-2016
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Elsevier BV
Date: 04-2015
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Jemma Hopewell.