Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists

Johnson, Andrew D.; Yanek, Lisa R.; Chen, Ming-Huei; Faraday, Nauder; Larson, Martin G.; Tofler, Geoffrey H.; Lin, Shiow J.; Kraja, Aldi T.; Province, Michael A.; Yang, Qiong; Becker, Diane M.; O’Donnell, Christopher J.; Becker, Lewis C.

doi:10.1038/ng.604

Cited by 248 publications

(274 citation statements)

References 48 publications

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“…19,[28][29][30] Interestingly, MRVI1 on chr11, another locus previously associated with platelet aggregation, 31 showed genetic overlap between migraine and IS, adding to previous data suggesting a shared role of platelet dysfunction in migraine and IS. 9 Mendelian randomization studies and interventional studies are needed to determine the exact role of platelets in mediating such genetic risk.…”

Section: Discovery Setmentioning

confidence: 85%

Shared genetic basis for migraine and ischemic stroke

Malik¹,

Freilinger²,

Winsvold³

et al. 2015

Neurology

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Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. Methods:We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. Results:We found substantial genetic overlap between migraine and IS using all 4 approaches.Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p 5 6.4 3 10 228 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p 5 2.7 3 10 220 for the CE score in MO). Conclusions:Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype. Neurology ® 2015;84:2132-2145 GLOSSARY CE 5 cardioembolic stroke; CPSM 5 cross-phenotype spatial mapping; GWAS 5 genome-wide association studies; IHGC 5 International Headache Genetics Consortium; IS 5 ischemic stroke; LAS 5 large artery stroke; LD 5 linkage disequilibrium; MA 5 migraine with aura; MO 5 migraine without aura; SNP 5 single nucleotide polymorphism; SVD 5 small vessel disease.Migraine is a primary headache disorder characterized by recurrent attacks of severe, often throbbing, headache associated with autonomic dysfunction. Although the majority of patients have migraine without aura (MO), one third have headaches preceded by transient neurologic disturbances (migraine with aura [MA]). 1 Ischemic stroke (IS) is etiologically heterogeneous and a leading cause of premature death and disability. Results of epidemiologic studies show increased risk of IS in migraine patients.3 A large metaanalysis of case-control and observational cohort studies reported an increased risk of IS for patients with MO and MA, 4 whereas more recent meta-analyses reported the association to be restricted to MA. 3,5,6 Pathophysiology linking these neurovascular disorders remains poorly understood; suggested mechanisms include cortical spreading depression, 7 endothelial dysfunction, 8 enhanced platelet activation, 9 and vasoconstriction.

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Section: Discovery Setmentioning

confidence: 85%

Shared genetic basis for migraine and ischemic stroke

Malik¹,

Freilinger²,

Winsvold³

et al. 2015

Neurology

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“…Interestingly, IRAG mutant platelets showed hyperaggregability upon agonist activation. Polymorphisms of Mrvi1, homologous to the human IRAG gene, were also associated with enhanced platelet aggregation in human patients (38). In vivo it was revealed that IRAG is a NO/cGMP/PKG1-dependent factor which thereby inhibited arterial thrombosis (2).…”

Section: Irag As Pkg Target: Signaling and Functionmentioning

confidence: 97%

IRAG and novel PKG targeting in the cardiovascular system

Schlossmann

Desch

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Schlossmann J, Desch M. IRAG and novel PKG targeting in the cardiovascular system. Am J Physiol Heart Circ Physiol 301: H672-H682, 2011. First published June 10, 2011; doi:10.1152/ajpheart.00198.2011.-Signaling by nitric oxide (NO) determines several cardiovascular functions including blood pressure regulation, cardiac and smooth muscle hypertrophy, and platelet function. NO stimulates the synthesis of cGMP by soluble guanylyl cyclases and thereby activates cGMP-dependent protein kinases (PKGs), mediating most of the cGMP functions. Hence, an elucidation of the PKG signaling cascade is essential for the understanding of the (patho)physiological aspects of NO. Several PKG signaling pathways were identified, meanwhile regulating the intracellular calcium concentration, mediating calcium desensitization or cytoskeletal rearrangement. During the last decade it emerged that the inositol trisphosphate receptor-associated cGMP-kinase substrate (IRAG), an endoplasmic reticulum-anchored 125-kDa membrane protein, is a main signal transducer of PKG activity in the cardiovascular system. IRAG interacts specifically in a trimeric complex with the PKG1␤ isoform and the inositol 1,4,5-trisphosphate receptor I and, upon phosphorylation, reduces the intracellular calcium release from the intracellular stores. IRAG motifs for phosphorylation and for targeting to PKG1␤ and 1,4,5-trisphosphate receptor I were identified by several approaches. The (patho)physiological functions for the regulation of smooth muscle contractility and the inhibition of platelet activation were perceived. In this review, the IRAG recognition, targeting, and function are summarized compared with PKG and several PKG substrates in the cardiovascular system. inositol trisphosphate receptor-associated guanosine 3=,5=-cyclic monophosphatekinase substrate; nitric oxide; guanosine 3=,5=-cyclic monophosphate-dependent protein kinase THIS ARTICLE is part of a collection on Hypertension and Novel Modulators of Vascular Tone. Other articles appearing in this collection, as well as a full archive of all collections, can be found online at http://ajpheart.physiology.org/.Nitric oxide (NO) leads to cGMP synthesis and thereby activates cGMP-dependent protein kinase (PKG), mediating various cardiovascular functions. The identification of PKG substrates including the inositol trisphosphate receptor-associated cGMP-kinase substrate (IRAG) has lead to a new view of PKG1 isozyme PKG1␤ and PKG1␣ function. Intracellular targeting and function of these isozymes are modulated by different substrates. The recognition of these substrates is mediated by the NH 2 -terminal leucine/isoleucine zipper (LZ) domains of PKG1. In this review the current view of the molecular interaction and function of IRAG compared with other substrates regulated by PKG are described, mainly focusing on the cardiovascular system. Furthermore, the subtle pathways for cGMP/PKG signaling are discussed. Function of NO/cGMP/PKG Signaling CascadeNO/cGMP signaling regulates several tasks in the cardiovascular sy...

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“…Recently, Jones et al (26), used a functional genomics approach to compare a relatively large number of SNPs (n = 1,327) in a selected group of candidate genes (n = 97), resulting in the identification of 17 independently associated SNPs that account for 48% of the variation in platelet reactivity induced by ADP. Even more recently, Johnson et al (27) performed a genome-wide meta-analysis of 2.5 million SNPs in 4,831 subjects to identify three loci associated with ADP-induced platelet aggregation.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel

Frelinger¹,

Michelson²,

Wiviott³

et al. 2011

Thromb Haemost

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SummaryIt was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y 12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y 12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, twophase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18-24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18-24 h and 15 day reactivity to ADP (correlations 0.24-0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y 12 blockade with high-dose clopidogrel or even higher level P2Y 12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.

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Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists

Cited by 248 publications

References 48 publications

Shared genetic basis for migraine and ischemic stroke

Shared genetic basis for migraine and ischemic stroke

IRAG and novel PKG targeting in the cardiovascular system

Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel

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