Faculty Collaboration Database

The ENTPD1 promoter polymorphism -860 A > G (rs3814159) is associated with increased gene transcription, protein expression, CD39/NTPDase1 enzymatic activity, and thromboembolism risk. FASEB J 2017 Jul;31(7):2771-2784

Date

03/18/2017

Pubmed ID

28302652

Pubmed Central ID

PMC6137499

DOI

10.1096/fj.201600344R

Scopus ID

2-s2.0-85021623731 (requires institutional sign-in at Scopus site)   6 Citations

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 the ENTPD1 gene (encoding NTPDase1) in 216 subjects then assessed genotypes in 2 cohorts comprising 2213 humans to identify ENTPD1 polymorphisms associated with venous thromboembolism (VTE). The G allele of the intron 1 polymorphism rs3176891 was more common in VTE vs. 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. The ENTPD1 promoter polymorphism -860 A > G (rs3814159) is associated with increased gene transcription, protein expression, CD39/NTPDase1 enzymatic activity, and thromboembolism risk.

Author List

Maloney JP, Branchford BR, Brodsky GL, Cosmic MS, Calabrese DW, Aquilante CL, Maloney KW, Gonzalez JR, Zhang W, Moreau KL, Wiggins KL, Smith NL, Broeckel U, Di Paola J

Authors

Brian Branchford MD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Alternative Splicing
Antigens, CD
Apyrase
Female
Gene Expression Regulation, Enzymologic
Genetic Predisposition to Disease
Genotype
HEK293 Cells
Humans
Male
Middle Aged
Polymorphism, Single Nucleotide
Venous Thromboembolism