rs6025 represents a SNP in the Factor V F5 gene, encoding a change in the protein from an arginine at position 506 to a glutamine. The resulting rs6025(A) allele encodes a mutation known as the Leiden mutation, R506Q, found in perhaps 3 to 5% of the individuals in most populations. About 1 in 10 individuals harboring the R506Q will experience clinically significant venous thromboembolism in their lifetimes (according to OMIM).
Overall, the rs6025(A) allele appears to be necessary but not sufficient for the development of venous thromboembolism. Patients who are rs6025(A;G) heterozygotes but lack other risk-enhancing SNPs have a risk of recurrent deep venous thrombosis equal to patients with no such SNPs. In contrast, patients who are heterozygotes for both rs6025 and the prothrombin rs1799963 SNP have a higher risk of recurrent thrombosis (relative risk, 2.6, CI: 1.3 to 5.1, p=0.002), and depending on other factors, this risk can climb to at least 5x. One study concludes that heterozygotes for rs6025 and rs1799963 have an increased risk of recurrent deep venous thrombosis after a first episode and are therefore candidates for lifelong anticoagulation treatment. [PMID 10477778]
More recent (and larger) studies have come to similar conclusions. In a study of over 9,000 Caucasian adults, rs6025(A;G) and rs6025(A;A) genotypes had 2.7x and 18x higher risk for venous thromboembolism, respectively, than rs6025(G;G) individuals. The lowest absolute 10-year risks for venous thromboembolism for (A;G) and (A;A) genotypes are 0.7% (CI: 0.5% to 1.0%) and 3% (CI: 1% to 8%) for nonsmokers younger than 40 years of age with a body mass index below 25 kg/m2, and the corresponding highest risks were 10% (CI: 7% to 14%) and 51% (CI: 13% to 100%) for overweight smokers over 60.[PMID 14996674]
Women who are pregnant and rs6025(A) carriers may be at risk for obstetric complications, including pre-eclampsia or venous thromboembolism, especially if they are also prothrombin rs1799963 heterozygotes and/or have a family history of thrombosis. One study concludes that if you assume an overall risk rate of 1 in 1500 pregnancies, the risk of thrombosis among rs6025(A) carriers by itself is 0.2 percent (1 in 500); among carriers of the prothrombin rs1799963(A) by itself, 0.5 percent (1 in 200); and among carriers of both variant SNPs, 4.6 percent (about 1 in 20).[PMID 10666427]
Women who are rs6025(A) carriers also are at increased risk for venous thromboembolism and perhaps ischemic stroke when they take combined oral contraceptives (i.e. "the pill"). A 2006 literature meta-analysis from a total of 10 studies concluded that "good" evidence existed for a greater risk of venous thromboembolism (risk ratios of 1.3-25.1) and cerebral vein or cerebral sinus thrombosis when comparing heterozygotes taking such contraceptives to heterozygotes who did not.[PMID 16413847]
Although preliminary, a 2010 study found that women taking tamoxifen as part of their treatment for early-stage breast cancer, those who had a thromboembolic event were nearly five times more likely to have a rs6025(A) allele compared to those who did not have a TE. The authors suggest that postmenopausal women should be evaluated for the rs6025(A) SNP before being given a prescription for tamoxifen if the result would affect the decision.[PMID 20554945] A related editorial points out that tamoxifen on its own is known to increase the risk of thromboembolic events 2-4 fold.[PMID 20554943]
|Disease Association||Defects in F5 are the cause of resistance to activated protein C (APCR) (MIM:188055). APCR is a form of thrombophilia. The APCR mutation is found in about 5% of the population which suggest that a slight thrombotic tendency may confer some advantage in fetal implantation.|
[PMID 19415820] The effect of nine common polymorphisms in coagulation factor genes (F2, F5, F7, F12 and F13 ) on the effectiveness of statins: the GenHAT study
[PMID 19786296] Platelet glycoprotein GP VI 13254C allele is an independent risk factor of premature myocardial infarction
[PMID 21291465] The association of genetic polymorphisms with cerebral palsy: a meta-analysis
[PMID 21564075] Resistance to activated protein C is a risk factor for pregnancy-related venous thrombosis in the absence of the F5 rs6025 (factor V Leiden) polymorphism
[PMID 21332313] Sequence variations in the FII, FV, F13A1, FGB and PAI-1 genes are associated with differences in myocardial perfusion
[PMID 21659962] Replication of genetic associations in the inflammation, complement, and coagulation pathways with intraventricular hemorrhage in LBW preterm neonates
[PMID 22198364] The association of inherited thrombophilia and intrauterine fetal death: a case-control study
[PMID 21913742] Genetic predictors of response to photodynamictherapy
[PMID 21955043] Validation of single nucleotide polymorphisms associated with acute rejection in kidney transplant recipients using a large multi-center cohort
[PMID 22421107] The G534E-polymorphism of the gene encoding the Factor VII-activating protease is a risk factor for venous thrombosis and recurrent events
[PMID 22707612] Genetic Risk Factors for Thrombosis in Systemic Lupus Erythematosus
|Disease||Thrombophilia due to factor V Leiden Ischemic stroke Budd-Chiari syndrome Recurrent abortion|
|CLNDBN||Thrombophilia due to factor V Leiden Ischemic stroke, susceptibility to Budd-Chiari syndrome, susceptibility to Recurrent abortion|
|CLNSRC||ClinVar GTR OMIM Allelic Variant|
|CLNACC||RCV000000674.1, RCV000000675.1, RCV000000676.1, RCV000023935.1,|
[PMID 16846490] Lemierre's syndrome and genetic polymorphisms: a case report.
[PMID 17048007] Association of warfarin dose with genes involved in its action and metabolism.
[PMID 17107626] Comparison of PrASE and Pyrosequencing for SNP Genotyping.
[PMID 17677000] Combined effects of thrombosis pathway gene variants predict cardiovascular events.
[PMID 18513389] New application of intelligent agents in sporadic amyotrophic lateral sclerosis identifies unexpected specific genetic background.
[PMID 18752569] Factor V Leiden is associated with pre-eclampsia but not with fetal growth restriction: a genetic association study and meta-analysis.
[PMID 18936436] Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991-1994.
[PMID 19131662] A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-alpha in nonhypertensive patients.
[PMID 19263529] Genetic risk factors in recurrent venous thromboembolism: A multilocus, population-based, prospective approach.
[PMID 19330901] Association of 77 polymorphisms in 52 candidate genes with blood pressure progression and incident hypertension: the Women's Genome Health Study.
[PMID 19536175] Follow-up of a major linkage peak on chromosome 1 reveals suggestive QTLs associated with essential hypertension: GenNet study.
[PMID 19538716] Thrombotic genetic risk factors and warfarin pharmacogenetic variants in Sao Miguel's healthy population (Azores).
[PMID 19559392] A candidate gene association study of 77 polymorphisms in migraine.
[PMID 19591822] Prevalence of genetic thrombophilic polymorphisms in the Sri Lankan population--implications for association study design and clinical genetic testing services.
[PMID 20031567] An evaluation of candidate genes of inflammation and thrombosis in relation to the risk of venous thromboembolism: The Women's Genome Health Study.
[PMID 20352152] Association of common genetic variations and idiopathic venous thromboembolism. Results from EDITh, a hospital-based case-control study.
[PMID 21422408] Clotting factor gene polymorphisms and colorectal cancer risk.
[PMID 22388798] Gene panels to help identify subgroups at high and low risk of coronary heart disease among those randomized to antihypertensive treatment: the GenHAT study.
[PMID 22540831] Candidate gene study of genetic thrombophilic polymorphisms in pre-eclampsia and recurrent pregnancy loss in Sinhalese women.
|Title||A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q.|
|Odds Ratio||3.5700 None|
[PMID 23015030] Differential haemostatic risk factors for pregnancy related deep vein thrombosis and pulmonary embolism. A population-based case-control study
[PMID 23018527] Necessity and risks of arterial blood sampling in healthy volunteer studies
|qualified_impact||Insufficiently evaluated pharmacogenetic|
[PMID 23132613] Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis
[PMID 23150947] Single nucleotide polymorphisms and the risk of venous thrombosis: results from a Danish case-cohort study
[PMID 23274712] Genetic polymorphisms and the risk of myocardial infarction in patients under 45 years of age.
[PMID 23533563] Novel risk factors for premature peripheral arterial occlusive disease in non-diabetic patients: a case-control study.
[PMID 24908450] A genetic association study of D-dimer levels with 50K SNPs from a candidate gene chip in four ethnic groups
[PMID 25028703] Maternal Genotype and Severe Preeclampsia: A HuGE Review
[PMID 25119470] Single Nucleotide Polymorphisms Other than Factor V Leiden Are Associated with Coagulopathy and Osteonecrosis of the Femoral Head in Chinese Patients
[PMID 25210051] Genetic Variations Associated with Recurrent Venous Thrombosis