Association of genetic variations with nonfatal venous thrombosis in postmenopausal women.
BACKGROUND
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.


METHODS
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).


METHODS
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.
Smith
Nicholas L
NL
Department of Epidemiology, University of Washington, Seattle, WA 98101, USA. nlsmith@u.washington.edu
Hindorff
Lucia A
LA
Heckbert
Susan R
SR
Lemaitre
Rozenn N
RN
Marciante
Kristin D
KD
Rice
Kenneth
K
Lumley
Thomas
T
Bis
Joshua C
JC
Wiggins
Kerri L
KL
Rosendaal
Frits R
FR
Psaty
Bruce M
BM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001777:Blood Coagulation / Q000235:genetics*; D019774:Blood Coagulation Factor Inhibitors / Q000235:genetics*; D001779:Blood Coagulation Factors / Q000235:genetics*; D016022:Case-Control Studies; D005165:Factor V / Q000235:genetics; D005172:Factor XI / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D047648:Perimenopause; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D011486:Protein C / Q000235:genetics; D012306:Risk; D020246:Venous Thrombosis / Q000453:epidemiology / Q000235:genetics*
D019774:Blood Coagulation Factor Inhibitors; D001779:Blood Coagulation Factors; D011486:Protein C; D005165:Factor V; D005172:Factor XI