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]
Coexistence of the R2 polymorphism rs1800595 with factor V Leiden increases the risk for venous thrombosis approximately to a 16-fold increased risk. The average age of the first thrombotic event is six years younger in individuals who are heterozygous for both factor V Leiden and the R2 polymorphism than in those with factor V Leiden alone. http://www.bloodjournal.org/content/94/9/3062?sso-checked=1
|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.|
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|CLNSRC||ClinVar GTR OMIM Allelic Variant|
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|Odds Ratio||3.5700 None|
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