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

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  • Additional Information
    • Source:
      Publisher: Lippincott, Williams & Wilkins Country of Publication: United States NLM ID: 7906255 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4563 (Electronic) Linking ISSN: 0194911X NLM ISO Abbreviation: Hypertension Subsets: MEDLINE
    • Publication Information:
      Publication: : Hagerstown, MD : Lippincott, Williams & Wilkins
      Original Publication: [Dallas, Tex.] : [American Heart Association], [©1979]-
    • Subject Terms:
      Genetic Predisposition to Disease* ; Polymorphism, Single Nucleotide*; Brain Ischemia/*genetics ; Cyclic Nucleotide Phosphodiesterases, Type 3/*genetics ; Endothelium, Vascular/*physiopathology ; Hypertension/*genetics ; Vasodilation/*physiology; Adolescent ; Adult ; Brain Ischemia/etiology ; Child ; Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism ; Female ; Follow-Up Studies ; Genetic Variation ; Humans ; Hypertension/complications ; Hypertension/metabolism ; Male ; Middle Aged ; Pregnancy ; Pregnancy Complications, Cardiovascular/genetics ; Pregnancy Complications, Cardiovascular/metabolism ; Pregnancy Complications, Cardiovascular/physiopathology ; Retrospective Studies ; Risk Factors ; Young Adult
    • Abstract:
      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.
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    • Grant Information:
      MC_EX_MR/M009203/1 United Kingdom MRC_ Medical Research Council; MC_PC_15018 United Kingdom MRC_ Medical Research Council; G9521010 United Kingdom MRC_ Medical Research Council; MR/M009203/1 United Kingdom MRC_ Medical Research Council; R01 NS103924 United States NS NINDS NIH HHS; G9815508 United Kingdom MRC_ Medical Research Council; RG/16/4/32218 United Kingdom BHF_ British Heart Foundation; K23 NS086873 United States NS NINDS NIH HHS; MC_PC_14089 United Kingdom MRC_ Medical Research Council; 102215/2/13/2 United Kingdom MRC_ Medical Research Council; MC_PC_19009 United Kingdom MRC_ Medical Research Council
    • Contributed Indexing:
      Keywords: cyclic nucleotide phosphodiesterases, type 3; genetics; genome-wide association study; stroke; vascular endothelium
    • Accession Number:
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
      EC 3.1.4.17 (PDE3A protein, human)
    • Publication Date:
      Date Created: 20191224 Date Completed: 20201021 Latest Revision: 20240726
    • Publication Date:
      20240726
    • Accession Number:
      PMC7055937
    • Accession Number:
      10.1161/HYPERTENSIONAHA.119.13513
    • Accession Number:
      31865795