Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Heart, Cohorts for; Starnet,; Study, UK Young Lacunar Dna

doi:10.1038/s41588-019-0449-0

Cited by 82 publications

(128 citation statements)

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“…9 MR analyses studying the effects of uric acid on cardiovascular disease and hypertension have previously been performed, with some supporting a causal association. [10][11][12] In addition, a recent MR study did not find an association between serum uric acid levels and Alzheimer disease risk, but other dementia types or cognitive function were not investigated. 13 Similarly, to our knowledge there is no published MR investigation of the role of uric acid on ischemic stroke and its subtypes.…”

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confidence: 99%

Genetically Determined Uric Acid and the Risk of Cardiovascular and Neurovascular Diseases: A Mendelian Randomization Study of Outcomes Investigated in Randomized Trials

Efstathiadou

Gill

McGrane

et al. 2019

JAHA

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BackgroundHigher serum uric acid levels are associated with cardiovascular and neurovascular disease, but whether these relationships are causal is not known. We applied Mendelian randomization approaches to assess the association between genetically determined uric acid levels and outcomes under study in large clinical trials.Methods and ResultsWe used 28 genetic variants related to serum uric acid as instruments to perform a range of 2‐sample Mendelian randomization methods. Our analysis had statistical power to detect clinically relevant effects of genetically determined serum uric acid levels on the considered clinical outcomes; cognitive function, Alzheimer disease, coronary heart disease, myocardial infarction, systolic blood pressure, and stroke. There was some suggestive evidence for an association between higher genetically determined serum uric acid and cognitive function. There was also some suggestive evidence of a relationship between coronary heart disease, systolic blood pressure, and the serum uric acid genetic instruments, but likely related to genetic pleiotropy. Overall, there was no consistent evidence of a clinically relevant effect of genetically determined serum uric acid on any of the considered outcomes.ConclusionsThis Mendelian randomization study does not support a clinically relevant causal effect of genetically determined serum urate on a range of cardiovascular and neurovascular outcomes. The weak association of genetically determined serum urate with coronary heart disease and systolic blood pressure may be because of pleiotropic effects. If urate lowering drugs such as allopurinol are found to affect these outcomes in clinical trials, then the effects may be mediated through urate independent mechanisms.

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confidence: 99%

Genetically Determined Uric Acid and the Risk of Cardiovascular and Neurovascular Diseases: A Mendelian Randomization Study of Outcomes Investigated in Randomized Trials

Efstathiadou

Gill

McGrane

et al. 2019

JAHA

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“…Therefore, we assessed the effect of known OSMR and LIFR eQTLs on coronary calcification (CAC) as intermediate phenotype of atherosclerotic burden, and primary cardiovascular outcomes as clinical manifestation. We queried summary statistics from GWAS on CAC (n=2,674)(45), coronary artery disease (CAD, n=336,755)(45,46), and ischemic stroke subtypes (sample sizes 242,573-522,258)(45–47). Neither eQTL associated with increased CAC burden, or cardiovascular disease susceptibility ( Supplemental Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

Common variants associated withOSMRexpression contribute to carotid plaque vulnerability, but not to cardiovascular disease in humans

Keulen

Koeverden

Boltjes

et al. 2019

Preprint

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BackgroundOncostatin M (OSM) signaling is implicated in atherosclerosis, however the mechanism remains unclear. We investigated the impact of common genetic variants in OSM and its receptors, OSMR and LIFR, on overall plaque vulnerability (based on macrophage, collagen, smooth muscle cell and fat content) and on seven individual atherosclerotic plaque phenotypes (calcification, collagen, atheroma size, macrophages, smooth muscle cells, vessel density and intraplaque hemorrhage). Methods and resultsWe queried Genotype-Tissue Expression (GTEx) data and selected one variant, rs13168867 (C allele), that associated with decreased OSMR expression and one variant, rs10491509 (A allele), that associated with increased LIFR expression in arterial tissue. No variant was associated to significantly altered OSM expression.We associated these two variants with plaque characteristics from 1,443 genotyped carotid endarterectomy patients in the Athero-Express Biobank Study. The rs13168867 variant in OSMR was significantly associated with an increased overall plaque vulnerability (β = 0.118 ± s.e. = 0.040, p = 3.00x10 -3 , C allele). With respect to different plaque phenotypes, this variant showed strongest associations with intraplaque fat (β = 0.248 ± s.e. = 0.088, p = 4.66x10 -3 , C allele) and collagen content (β = -0.259 ± s.e. = 0.095, p = 6.22x10 -3 , C allele). No associations were found for rs10491509 in the LIFR locus. ConclusionOur study suggests that genetically decreased arterial OSMR expression, possibly resulting in decreased OSM signaling, contributes to increased carotid plaque vulnerability.

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“…The immune system might be a novel target for the development of new therapeutic agents for VTE and PAD. The 25 most relevant Reactome pathways (https://reactome.org) 7 according to genome wide association study (GWAS) associated genes for venous thromboembolism (VTE), 1 peripheral artery disease (PAD), 2 stroke, 8 and coronary artery disease (CAD). 9…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…It could also be used to formulate predictive models of normal and disease pathways. 7 We used risk loci (or nearest loci) as reported in GWAS for VTE, 1 PAD, 2 stroke, 8 and CAD. 9 In Figure 1 are presented the 25 most relevant pathways identified for VTE, PAD, stroke, and CAD by a Reactome pathway analysis based on reported genes from GWAS of VTE, PAD, stroke and CAD.…”

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Reactome Pathway Analysis of Venous Thromboembolism, Peripheral Artery Disease, Stroke, and Coronary Artery Disease

et al. 2020

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Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

Cited by 82 publications

References 0 publications

Genetically Determined Uric Acid and the Risk of Cardiovascular and Neurovascular Diseases: A Mendelian Randomization Study of Outcomes Investigated in Randomized Trials

Genetically Determined Uric Acid and the Risk of Cardiovascular and Neurovascular Diseases: A Mendelian Randomization Study of Outcomes Investigated in Randomized Trials

Common variants associated withOSMRexpression contribute to carotid plaque vulnerability, but not to cardiovascular disease in humans

Reactome Pathway Analysis of Venous Thromboembolism, Peripheral Artery Disease, Stroke, and Coronary Artery Disease

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