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Influence of Genetic Variation in PDE3A on Endothelial Function and Stroke.

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Traylor, Matthew 
Amin Al Olama, Ali 
Lyytikäinen, Leo-Pekka 
Marini, Sandro 
Chung, Jaeyoon 


We aimed to characterize the genetics of endothelial function and how this influences risk for cardiovascular diseases such as ischemic stroke. We integrated genetic data from a study of ultrasound flow-mediated dilatation of brachial artery in adolescents from ALSPAC (Avon Longitudinal Study of Parents and Children; n=5214) with a study of ischemic stroke (MEGASTROKE: n=60 341 cases and 452 969 controls) to identify variants that confer risk of ischemic stroke through altered endothelial function. We identified a variant in PDE3A (Phosphodiesterase 3A), encoding phosphodiesterase 3A, which was associated with flow-mediated dilatation in adolescents (9-12 years of age; β[SE], 0.38 [0.070]; P=3.8×10-8) and confers risk of ischemic stroke (odds ratio, 1.04 [95% CI, 1.02-1.06]; P=5.2×10-6). Bayesian colocalization analyses showed the same underlying variation is likely to lead to both associations (posterior probability, 97%). The same variant was associated with flow-mediated dilatation in a second study in young adults (age, 24-27 years; β[SE], 0.47 [0.23]; P=0.047) but not in older adults (β[SE], -0.012 [0.13]; P=0.89). We conclude that a genetic variant in PDE3A influences endothelial function in early life and leads to increased risk of ischemic stroke. Subtle, measurable changes to the vasculature that are influenced by genetics also influence risk of ischemic stroke.



cyclic nucleotide phosphodiesterases, type 3, genetics, genome-wide association study, stroke, vascular endothelium, Adolescent, Adult, Brain Ischemia, Child, Cyclic Nucleotide Phosphodiesterases, Type 3, Endothelium, Vascular, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genetic Variation, Humans, Hypertension, Male, Middle Aged, Polymorphism, Single Nucleotide, Pregnancy, Pregnancy Complications, Cardiovascular, Retrospective Studies, Risk Factors, Vasodilation, Young Adult

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Ovid Technologies (Wolters Kluwer Health)


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European Commission Horizon 2020 (H2020) Societal Challenges (667375)
British Heart Foundation (RG/16/4/32218)
Medical Research Council (MC_PC_14089)
This study was supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 667375. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Matthew Traylor and Hugh Markus will serve as guarantors for the contents of this paper. This work was supported by a British Heart Foundation Programme Grant (RG/16/4/32218). Hugh Markus is supported by a National Institute for Health Research (NIHR) Senior Investigator award, and his work is supported by the Cambridge Universities NIHR Comprehensive Biomedical Research Centre. Dr. Anderson is supported by NIH R01NS103924 and K23NS086873. The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research ; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (grant 755320 for TAXINOMISIS); European Research Council (grant 742927 for MULTIEPIGEN project); and Tampere University Hospital Supporting Foundation.