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Nicholas L. Smith, PhD, MPH; Lucia A. Hindorff, PhD; Susan R. Heckbert, MD, PhD; Rozenn N. Lemaitre, PhD, MPH; Kristin D. Marciante, PhD; Kenneth Rice, PhD; Thomas Lumley, PhD; Joshua C. Bis, MS; Kerri L. Wiggins, MS, RD; Frits R. Rosendaal, MD, PhD; Bruce M. Psaty, MD, PhD

JAMA. 2007;297:489-498.

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.

Author Affiliations: Departments of Epidemiology (Drs Smith, Hindorff, Heckbert, and Psaty and Mr Bis), Medicine (Drs Lemaitre, Marciante, and Psaty and Ms Wiggins), Biostatistics (Drs Rice and Lumley), and Health Services (Dr Psaty), University of Washington, Seattle; and Departments of Clinical Epidemiology and Hematology, Leiden University Medical Center, Leiden, the Netherlands (Dr Rosendaal).

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