Smith Nicholas L, Hindorff Lucia A, Heckbert Susan R, Lemaitre Rozenn N, Marciante Kristin D, Rice Kenneth, Lumley Thomas, Bis Joshua C, Wiggins Kerri L, Rosendaal Frits R, Psaty Bruce M
Department of Epidemiology, University of Washington, Seattle, WA 98101, USA.
JAMA. 2007 Feb 7;297(5):489-98. doi: 10.1001/jama.297.5.489.
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.
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).
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.
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.
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.
尽管激活或抑制纤维蛋白生成及溶解的凝血蛋白和酶的作用已得到充分表征，但这些成分的基因变异对静脉血栓形成（VT）风险的潜在影响尚未得到充分研究。
描述24个凝血、抗凝、纤维蛋白溶解和抗纤维蛋白溶解候选基因的常见基因变异与绝经后妇女非致命性VT发生风险的关联。
设计、地点和参与者：在华盛顿州一个大型综合医疗保健系统中进行的基于人群的病例对照研究。参与者为年龄在30至89岁之间的围绝经期和绝经后妇女，她们在1995年1月至2002年12月期间首次发生VT事件（n = 349），以及1680名在年龄、高血压状态和日历年份上匹配的对照（n = 1680）。
通过常见单倍型以及个体单倍型和单核苷酸多态性（SNP）测量的与基因内整体变异相关的静脉血栓形成风险。通过错误发现率q值的0.20阈值评估关联的显著性，该阈值考虑了多重检验。
只有组织因子途径抑制基因显示出与风险的整体关联（q = 0.13）。在SNP分析中，在3个候选基因（因子V、XI和蛋白C）中鉴定出5个显著的SNP关联。其中2个关联先前已有报道。另外15个基因中的22个变异的P值小于0.05，但q值在0.20至0.35之间。其中5个证实了先前报道的关联（纤维蛋白原基因和蛋白C），2个与早期报道不一致（血栓调节蛋白和纤溶酶原激活物抑制剂1），15个是新发现。
在考虑多重检验后，鉴定出5个与VT风险相关的SNP，其中3个先前未被报道。有必要在其他人群中复制这些新的关联，以证实这些发现，并确定哪些遗传因素可能影响绝经后妇女的VT风险。
