Influence of Genetic Variation in PDE3A on Endothelial Function and Stroke

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.

[1]  Dajiang J. Liu,et al.  Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use , 2018, Nature Genetics.

[2]  Andrew D. Johnson,et al.  GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes , 2018, Nature Communications.

[3]  Anthony J. Payne,et al.  Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps , 2018, Nature Genetics.

[4]  Jay A. Montgomery,et al.  Multi-ethnic genome-wide association study for atrial fibrillation , 2018, Nature Genetics.

[5]  B. Kim,et al.  Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial , 2018, The Lancet Neurology.

[6]  Andrew D. Johnson,et al.  Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes , 2018, Nature Genetics.

[7]  Pim van der Harst,et al.  Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease , 2017, Circulation research.

[8]  P. Donnelly,et al.  Genome-wide genetic data on ~500,000 UK Biobank participants , 2017, bioRxiv.

[9]  Andrew D. Johnson,et al.  Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms , 2017, Nature Genetics.

[10]  Christian Gieger,et al.  Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets , 2017, Nature Genetics.

[11]  He Gao,et al.  Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk , 2017, Nature Genetics.

[12]  Joseph K. Pickrell,et al.  Detection and interpretation of shared genetic influences on 42 human traits , 2015, Nature Genetics.

[13]  Mitchell J. Machiela,et al.  LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants , 2015, Bioinform..

[14]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[15]  Carson C Chow,et al.  Second-generation PLINK: rising to the challenge of larger and richer datasets , 2014, GigaScience.

[16]  J. Pankow,et al.  Multi-ethnic analysis reveals soluble l-selectin may be post-transcriptionally regulated by 3′UTR polymorphism: the Multi-Ethnic Study of Atherosclerosis (MESA) , 2015, Human Genetics.

[17]  K. Lunetta,et al.  PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation , 2014, Annals of neurology.

[18]  J. Horowitz,et al.  Aging of the Nitric Oxide System: Are We as Old as Our NO? , 2014, Journal of the American Heart Association.

[19]  Matthew A. Hibbs,et al.  Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment , 2014, PLoS genetics.

[20]  C. Iadecola,et al.  The Pathobiology of Vascular Dementia , 2013, Neuron.

[21]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[22]  D. Lawlor,et al.  Cohort Profile: The ‘Children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children , 2012, International journal of epidemiology.

[23]  D. Lawlor,et al.  Cohort Profile: The Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort , 2012, International journal of epidemiology.

[24]  Amir Lerman,et al.  The Assessment of Endothelial Function: From Research Into Clinical Practice , 2012, Circulation.

[25]  Y. Ohashi,et al.  Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial , 2010, The Lancet Neurology.

[26]  D. Altshuler,et al.  A map of human genome variation from population-scale sequencing , 2010, Nature.

[27]  D. Lawlor,et al.  Determinants of vascular phenotype in a large childhood population: the Avon Longitudinal Study of Parents and Children (ALSPAC). , 2010, European heart journal.

[28]  Ryan A. Harris,et al.  Ultrasound Assessment of Flow-Mediated Dilation , 2010, Hypertension.

[29]  M. Marmot,et al.  Endothelial Function Predicts Progression of Carotid Intima-Media Thickness , 2009, Circulation.

[30]  Risto Telama,et al.  Cohort profile: the cardiovascular risk in Young Finns Study. , 2008, International journal of epidemiology.

[31]  H. Markus.  Genes, endothelial function and cerebral small vessel disease in man , 2008, Experimental physiology.

[32]  T. Rabelink,et al.  Endothelial function and dysfunction: testing and clinical relevance. , 2007, Circulation.

[33]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[34]  S. Kwon,et al.  Cilostazol Prevents the Progression of the Symptomatic Intracranial Arterial Stenosis: The Multicenter Double-Blind Placebo-Controlled Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis , 2005, Stroke.

[35]  R. Busse,et al.  Endothelial aging. , 2005, Cardiovascular research.

[36]  J. Viikari,et al.  Interrelations Between Brachial Endothelial Function and Carotid Intima-Media Thickness in Young Adults: The Cardiovascular Risk in Young Finns Study , 2004, Circulation.

[37]  M. Crow,et al.  Age-related changes in the signaling and function of vascular smooth muscle cells , 1999, Experimental Gerontology.