CONTEXT: Although the roles of clotting proteins and enzymes that activate or inhibit fibrin production and lysis are well characterized, the underlying contribution of genetic variation in these constituents to risk of venous thrombosis (VT) has not been fully investigated. OBJECTIVE: To describe the association of common genetic variation in 24 coagulation, anticoagulation, fibrinolysis, and antifibrinolysis candidate genes with risk of incident nonfatal VT in postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS: Population-based case-control study conducted in a large integrated health care system in Washington State. Participants were perimenopausal and postmenopausal women aged 30 to 89 years who sustained a first VT event between January 1995 and December 2002 (n = 349) and 1680 controls matched on age, hypertension status, and calendar year (n = 1680). MAIN OUTCOME MEASURE: Risk of venous thrombosis associated with global variation within a gene as measured by common haplotypes and with individual haplotypes and single nucleotide polymorphisms (SNPs). Significance of the associations was assessed by a .20 threshold of the false-discovery rate q value, which accounts for multiple testing. RESULTS: Only the tissue factor pathway inhibitor gene demonstrated global association with risk (q = .13). Five significant SNP associations were identified across 3 of the candidate genes (factors V, XI, and protein C) in SNP analyses. Two associations have been previously reported. Another 22 variants across 15 genes had P values less than .05 but q values between .20 and .35. Five of these confirm previously reported associations (fibrinogen genes and protein C), 2 were inconsistent with earlier reports (thrombomodulin and plasminogen activator inhibitor 1), and 15 were new discoveries. CONCLUSIONS: After accounting for multiple testing, 5 SNPs associated with VT risk were identified, 3 of which have not been previously reported. Replication of these novel associations in other populations is necessary to corroborate these findings and identify which genetic factors may influence VT risk in postmenopausal women.
CONTEXT: Although the roles of clotting proteins and enzymes that activate or inhibit fibrin production and lysis are well characterized, the underlying contribution of genetic variation in these constituents to risk of venous thrombosis (VT) has not been fully investigated. OBJECTIVE: To describe the association of common genetic variation in 24 coagulation, anticoagulation, fibrinolysis, and antifibrinolysis candidate genes with risk of incident nonfatal VT in postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS: Population-based case-control study conducted in a large integrated health care system in Washington State. Participants were perimenopausal and postmenopausal women aged 30 to 89 years who sustained a first VT event between January 1995 and December 2002 (n = 349) and 1680 controls matched on age, hypertension status, and calendar year (n = 1680). MAIN OUTCOME MEASURE: Risk of venous thrombosis associated with global variation within a gene as measured by common haplotypes and with individual haplotypes and single nucleotide polymorphisms (SNPs). Significance of the associations was assessed by a .20 threshold of the false-discovery rate q value, which accounts for multiple testing. RESULTS: Only the tissue factor pathway inhibitor gene demonstrated global association with risk (q = .13). Five significant SNP associations were identified across 3 of the candidate genes (factors V, XI, and protein C) in SNP analyses. Two associations have been previously reported. Another 22 variants across 15 genes had P values less than .05 but q values between .20 and .35. Five of these confirm previously reported associations (fibrinogen genes and protein C), 2 were inconsistent with earlier reports (thrombomodulin and plasminogen activator inhibitor 1), and 15 were new discoveries. CONCLUSIONS: After accounting for multiple testing, 5 SNPs associated with VT risk were identified, 3 of which have not been previously reported. Replication of these novel associations in other populations is necessary to corroborate these findings and identify which genetic factors may influence VT risk in postmenopausal women.
Authors: Weihong Tang; Christine Schwienbacher; Lorna M Lopez; Yoav Ben-Shlomo; Tiphaine Oudot-Mellakh; Andrew D Johnson; Nilesh J Samani; Saonli Basu; Martin Gögele; Gail Davies; Gordon D O Lowe; David-Alexandre Tregouet; Adrian Tan; James S Pankow; Albert Tenesa; Daniel Levy; Claudia B Volpato; Ann Rumley; Alan J Gow; Cosetta Minelli; John W G Yarnell; David J Porteous; John M Starr; John Gallacher; Eric Boerwinkle; Peter M Visscher; Peter P Pramstaller; Mary Cushman; Valur Emilsson; Andrew S Plump; Nena Matijevic; Pierre-Emmanuel Morange; Ian J Deary; Andrew A Hicks; Aaron R Folsom Journal: Am J Hum Genet Date: 2012-06-14 Impact factor: 11.025
Authors: Weihong Tang; Saonli Basu; Xiaoxiao Kong; James S Pankow; Nena Aleksic; Adrian Tan; Mary Cushman; Eric Boerwinkle; Aaron R Folsom Journal: Blood Date: 2010-08-27 Impact factor: 22.113
Authors: Nicholas L Smith; Kenneth M Rice; Edwin G Bovill; Mary Cushman; Joshua C Bis; Barbara McKnight; Thomas Lumley; Nicole L Glazer; Astrid van Hylckama Vlieg; Weihong Tang; Abbas Dehghan; David P Strachan; Christopher J O'Donnell; Jerome I Rotter; Susan R Heckbert; Bruce M Psaty; Frits R Rosendaal Journal: Blood Date: 2010-12-16 Impact factor: 22.113
Authors: Irene D Bezemer; Andre R Arellano; Carmen H Tong; Charles M Rowland; Helen A Ireland; Kenneth A Bauer; Joseph Catanese; Pieter H Reitsma; Carine J M Doggen; James J Devlin; Frits R Rosendaal; Lance A Bare Journal: Haematologica Date: 2009-03-13 Impact factor: 9.941
Authors: Aaron R Folsom; Weihong Tang; Kristen M George; Susan R Heckbert; Richard F MacLehose; Mary Cushman; James S Pankow Journal: Thromb Res Date: 2016-01-12 Impact factor: 3.944
Authors: Weihong Tang; Martina Teichert; Daniel I Chasman; John A Heit; Pierre-Emmanuel Morange; Guo Li; Bruno H Ch Stricker; Paul M Ridker; Aaron R Folsom; Nicholas L Smith; Nathan Pankratz; Frank W Leebeek; Guillaume Paré; Mariza de Andrade; Christophe Tzourio; Bruce M Psaty; Saonli Basu; Rikje Ruiter; Lynda Rose; Sebastian M Armasu; Thomas Lumley; Susan R Heckbert; André G Uitterlinden; Mark Lathrop; Kenneth M Rice; Mary Cushman; Albert Hofman; Jean-Charles Lambert; Nicole L Glazer; James S Pankow; Jacqueline C Witteman; Philippe Amouyel; Joshua C Bis; Edwin G Bovill; Xiaoxiao Kong; Russell P Tracy; Eric Boerwinkle; Jerome I Rotter; David-Alexandre Trégouët; Daan W Loth Journal: Genet Epidemiol Date: 2013-05-05 Impact factor: 2.135
Authors: Robert C Kaplan; Nicholas L Smith; Stanley Zucker; Susan R Heckbert; Kenneth Rice; Bruce M Psaty Journal: Atherosclerosis Date: 2008-03-14 Impact factor: 5.162