title: TheENTPD1promoter polymorphism -860 A > G (rs3814159) is associated with increased gene transcription, protein expression, CD39/NTPDase1 enzymatic activity, and thromboembolism risk.
abstract: Ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1) degrades the purines ATP and ADP that are key regulators of inflammation and clotting. We hypothesized that NTPDase1 polymorphisms exist and that they regulate this pathway. We sequenced theENTPD1gene (encoding NTPDase1) in 216 subjects then assessed genotypes in 2 cohorts comprising 2213 humans to identifyENTPD1polymorphisms associated with venous thromboembolism (VTE). The G allele of the intron 1 polymorphism rs3176891 was more common in VTEvs.controls (odds ratio 1.26-1.9); it did not affect RNA splicing, but it was in strong linkage disequilibrium with the G allele of the promoter polymorphism rs3814159, which increased transcriptional activity by 8-fold. Oligonucleotides containing the G allele of this promoter region bound nuclear extracts more avidly. Carriers of rs3176891 G had endothelial cells with increased NTPDase1 activity and protein expression, and had platelets with enhanced aggregation. Thus, the G allele of rs3176891 marks a haplotype associated with increased clotting and platelet aggregation attributable to a promoter variant associated with increased transcription, expression, and activity of NTPDase1. We term this gain-of-function phenotype observed with rs3814159 G "CD39 Denver."-Maloney, J. P., Branchford, B. R., Brodsky, G. L., Cosmic, M. S., Calabrese, D. W., Aquilante, C. L., Maloney, K. W., Gonzalez, J. R., Zhang, W., Moreau, K. L., Wiggins, K. L., Smith, N. L., Broeckel, U., Di Paola, J. TheENTPD1promoter polymorphism -860 A > G (rs3814159) is associated with increased gene transcription, protein expression, CD39/NTPDase1 enzymatic activity, and thromboembolism risk.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Colorado at Denver, Aurora, Colorado, USA; james.maloney@ucdenver.edu.|Denver Veterans Affairs Medical Center, Denver, Colorado, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Maloney
authors.affiliation: Center for Cancer and Blood Disorders, University of Colorado at Denver, Aurora, Colorado, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Branchford
authors.affiliation: Center for Cancer and Blood Disorders, University of Colorado at Denver, Aurora, Colorado, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Brodsky
authors.affiliation: Chest, Infectious Disease, and Critical Care Associates, Des Moines, Iowa, USA.
authors.forename: Maxwell S
authors.initials: MS
authors.lastname: Cosmic
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Colorado at Denver, Aurora, Colorado, USA.|Denver Veterans Affairs Medical Center, Denver, Colorado, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Calabrese
authors.affiliation: Pharmaceutical Sciences/School of Pharmacy, University of Colorado at Denver, Aurora, Colorado, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Aquilante
authors.affiliation: Center for Cancer and Blood Disorders, University of Colorado at Denver, Aurora, Colorado, USA.
authors.forename: Kelly W
authors.initials: KW
authors.lastname: Maloney
authors.affiliation: Otolaryngology-Head and Neck Surgery, University of Colorado at Denver, Aurora, Colorado, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Gonzalez
authors.affiliation: Biostatistics and Informatics/Colorado School of Public Health, University of Colorado at Denver, Aurora, Colorado, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Division of Geriatric Medicine, University of Colorado at Denver, Aurora, Colorado, USA.
authors.forename: Kerrie L
authors.initials: KL
authors.lastname: Moreau
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Kerri L
authors.initials: KL
authors.lastname: Wiggins
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington, USA.|Seattle Epidemiologic Research and Information Center, Seattle, Washington, USA.|Veterans Affairs Office of Research and Development, Seattle, Washington, USA.|Group Health Research Institutes, Group Health Cooperative, Seattle, Washington, USA.
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Smith
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.|Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.|Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Broeckel
authors.affiliation: Center for Cancer and Blood Disorders, University of Colorado at Denver, Aurora, Colorado, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Di Paola
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001081:Apyrase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054556:Venous Thromboembolism / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D001081:Apyrase; C067869:CD39 antigen
keywords: CD39 Denver; P2Y1; platelet aggregation; purinergic signaling