Common hemostasis and inflammation gene variants and venous thrombosis in older adults from the Cardiovascular Health Study

Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
Journal of Thrombosis and Haemostasis (Impact Factor: 5.72). 06/2009; 7(9):1499-505. DOI: 10.1111/j.1538-7836.2009.03522.x
Source: PubMed


Age-related changes in blood coagulation and fibrinolysis are associated with increased risk of thrombotic events. Inherited deficiencies of coagulation proteins, such as factor V (FV) Leiden and prothrombin G20210A, explain a small fraction of venous thromboembolic disease (VTE). Additional genetic factors are likely to underlie the etiology of VTE, some of which may become manifest at older ages.
We tested 290 common SNPs within 51 thrombosis and inflammation genes for association with VTE in the Cardiovascular Health Study, a large, prospective cohort of older adults followed for up to 12 years.
There were 184 VTE events that occurred at mean age of 78 years. TagSNPs within four genes encoding FXIII subunit A (F13A), FVII activating protease (HABP2), protease activated receptor-1 (F2R) and the urokinase receptor (PLAUR) showed the strongest evidence for association with VTE, with each gene having a global P-value < 0.05 and at least one tagSNP false discovery rate (FDR) q-value < 0.05. The rs3024409 variant allele of F13A1 was associated with 1.66-fold increased risk of VTE, while the minor alleles of HABP2 rs6585234 and rs3862019, F2R rs253061 and rs153311, and PLAUR rs344782 were each associated with lower risk of VTE (hazard ratios in the range of 0.49-0.66). Consistent with the observed protective association for VTE risk, the HABP2 rs3862019 variant allele was also associated with lower activity levels of coagulation factors FVIII, FIX, FX and plasminogen. We also confirm previously reported associations between common variants of the coagulation FII, FV, FVIII, FXI, alpha-fibrinogen and protein C genes and risk of VTE.
These findings suggest that several novel common coagulation gene variants may be related to risk of VTE in older adults. Further studies in older adults are needed to validate these findings and assess functional molecular mechanisms.

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    • "In this context, coexistence of heterozygous FVL mutation and the G20210A mutation in the prothrombin gene is the most frequent abnormality causing VTE [35] [36]. Moreover, combinations of FVL, antithrombin , protein C or protein S deficiencies and hyperhomocystienemia , have been found to result in a 5-to-10 fold increase in the relative risk of thrombosis (see Table 1-adapted from " Natural anticoagulants and thrombophilia " ) [37] [38]. "
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    ABSTRACT: Factor V Leiden, is a variant of human factor V (FV), also known as proaccelerin, which leads to a hypercoagulable state. Along these years, factor V Leiden (FVL) has been studied from the pathophysiologic point of view, and research has been focused on finding clinical approaches for the management of the FVL associated to a trombophilic state. Less attention has been paid about the possible role of FVL in inflammatory conditions known to be present in different disorders such as uremia, cirrhosis, liver transplantation, depression as well as sepsis, infection or, inflammatory bowel disease (IBD). Whether platelet FVL will increase the activation of coagulation and/or in which proportion is able to determine the final outcome in the previously mentioned inflammatory conditions is a subject that remains uncertain. This paper will review the association of FVL with inflammation. Specifically, it will analyze the important role of the endothelium and the contribution of other inflammatory components involved at both the immune and vascular levels. This paper will also try to emphasize the importance of being a FVL carrier in associations to diseases where a chronic inflammation occurs, and how this condition may be determinant in the progression and outcome of a specific clinic situation.
    Full-text · Article · May 2012
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    • "Some SNPs in genes encoding proteins outside the coagulation pathway were also associated with VT in these studies, for example, nuclear receptor subfamily 1, group I, member 2 (NR1I2, also termed pregnane X receptor ), N-acetyltransferase 8B (NAT8B), regulator of G-protein signalling 7 (RGS7), and human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1) (Bezemer et al, 2008; Morange et al, 2010). Three studies have reported association of VT with other SNPs in candidate genes related to coagulation or inflammation with diverging results (Smith et al, 2007, 2009; Reiner et al, 2009; Zee et al, 2009). The mechanism behind pregnancy-related VT is multicausal , including hormonal changes, mechanical pressure on the iliac vein due to the enlarged uterus, and the trauma of giving birth. "
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    ABSTRACT: Venous thrombosis (VT) is one of the leading causes of maternal death in the western world, but the genetic causes of pregnancy-related VT are insufficiently understood. The aim of this study was to investigate the association between common genetic variations in candidate genes and pregnancy-related VT. We undertook a hospital based case-control study of women with VT during pregnancy or puerperium; controls were women giving birth without having VT. Single nucleotide polymorphisms (SNPs) were selected in 49 pre-specified candidate genes involved in coagulation, inflammation, and hormonal metabolism in 313 cases and 353 controls. We found new associations between SNPs and total pregnancy-related VT in the genes encoding coagulation factors V and VIII, and p-selectin. Additional new associations between SNPs and antenatal VT were found in the genes encoding the epidermal growth factor receptor, the pregnane X receptor, and protein S. Of 21 SNPs previously associated with thrombotic disease, rs2289252 in F11 and rs3917643 in F3 were associated with pregnancy-related VT, while rs4524 in F5 was associated with antenatal VT.
    Full-text · Article · Apr 2012 · British Journal of Haematology
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    • "of variants of different genes with environmental factors may be relatively unpredictable at an individual level. There is proof of principle that multiple SNP testing (single nucleotide polymorphisms) quantifies the risk of recurrent VTE (van Hylckama Vlieg et al., 2008) and the number of common coagulation gene variants shown to be possibly related to risk of VTE is increasing (Bezemer et al., 2008; Reiner et al., 2009). "
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    ABSTRACT: Characterisation of heritable thrombophilic defects has facilitated an understanding of the complex mechanisms influencing risk of venous thromboembolism. In parallel with this, the importance of gene-environment interaction in the development of this disease has become apparent. However, testing for a limited number of heritable thrombophilic defects (first generation thrombophilia testing) has not been shown to predict likelihood of recurrent venous thrombosis to any useful degree. This paradox whereby thrombophilia testing identifies defects associated with an increased risk of a first venous thrombosis but not of a particularly high risk of recurrence is likely the result of limitations imposed by a limited dichotomous testing strategy compounded by test inaccuracy and imprecision. Consequently, the observed intermediate phenotype (defined by limited dichotomous testing) is not concordant with the risk of recurrent venous thrombosis. Whilst a simple dichotomous testing strategy for a limited number of heritable thrombophilic defects has not been shown to have useful clinical predictive value, proof-of-principle is emerging for testing of multiple genetic factors in predicting the likelihood of recurrent thrombosis. In addition, recent studies indicate that measurement of the global activity of the coagulation system using either biomarkers or measuring the thrombin generating potential (second generation thrombophilia testing) may have useful clinical predictive value for recurrent thrombosis. The assessment of the intermediate phenotype by global coagulation tests and genome-wide mutation and SNP (single nucleotide polymorphisms) detection may provide complimentary approaches to the quantification of risk of recurrence and enable a move towards more patient-focussed rather than disease-focussed care.
    Preview · Article · Aug 2011 · International journal of laboratory hematology
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