rs6025

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. This mutation is often referred to as the G1691A or 1691G-A change. See the OMIM entry In a 2017 study using UK Biobank, based on 3290 VTE cases and 116 868 controls, the odds ratio for a polymorphism involving the minor risk allele was 3.5. They also found higher odds for venous thromboembolism in overweight individuals (+1.57 for every 1 SD higher BMI). In a 2013 meta-analysis of 31 databases, the analysis of Factor V rs6025 variants was based on 9,081 cases and 17,513 controls. The polymorphic variant risk for Venous Thromboembolism was overall OR: 4.38. The risk was greater in younger subjects (<45 years old, OR: 5.43; ≥45 years old, OR: 3.71). Slightly higher risk appeared in men (OR: 5.06) and in women taking oral contraceptives (OR: 6.10). The AG polymorphic variant was associated with recurrent thrombosis (recurrent VTE event, OR: 5.81; no recurrence reported, OR: 3.95). The higher risks were for venous thrombosis without evidence of pulmonary embolism (OR: 4.49) or a cerebral venous sinus thrombosis (OR: 4.14). The AA homozygous variant was rarer, and its risk was significantly higher at 11.45 but was based on fewer individuals (116 subjects among cases and 24 controls). Independent risk was seen in variants of the PT20210A or Factor 2 SNP at i3002432 (also known as rs1799963 ) Other studies have come to similar conclusions. In a 2004 study of over 9,000 Caucasian adults in the Danish population, 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 were 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. In a study done in the year 2000 on 119 women, it was found that women who are pregnant and rs6025(A) carriers could be at risk for obstetric complications, including pre-eclampsia or venous thromboembolism, especially if they were also prothrombin rs1799963 heterozygotes and/or have a family history of thrombosis. They concluded that if you assume an overall risk rate of 1 in 1500 pregnancies, the risk of thrombosis among rs6025(A) carriers by itself would be 0.2 percent (1 in 500); among carriers of the prothrombin rs1799963(A) by itself, would be 0.5 percent (1 in 200); and among carriers of both variant SNPs, 4.6 percent (about 1 in 20). A 2006 review article of 10 previous studies found that 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. Additionally, a 2004 meta-analysis involving 18,000 cases and 58,000 controls found an increased risk for ischemic stroke for rs6025(A) carriers. The odds ratio based on a study of ~4,500 patients was 1.33, CI: 1.12-1.58. 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. A related editorial pointed out that tamoxifen on its own is known to increase the risk of thromboembolic events 2-4 fold. According to a 1999 Blood journal article, coexistence of the R2 polymorphism rs1800595 with factor V Leiden increased 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. bloodjournal.org Another 1999 study concluded 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. Lemierre's syndrome and genetic polymorphisms: a case report. Association of warfarin dose with genes involved in its action and metabolism. Comparison of PrASE and Pyrosequencing for SNP Genotyping. Combined effects of thrombosis pathway gene variants predict cardiovascular events. New application of intelligent agents in sporadic amyotrophic lateral sclerosis identifies unexpected specific genetic background. Factor V Leiden is associated with pre-eclampsia but not with fetal growth restriction: a genetic association study and meta-analysis. Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991-1994. A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-alpha in nonhypertensive patients. Genetic risk factors in recurrent venous thromboembolism: A multilocus, population-based, prospective approach. Association of 77 polymorphisms in 52 candidate genes with blood pressure progression and incident hypertension: the Women's Genome Health Study. Follow-up of a major linkage peak on chromosome 1 reveals suggestive QTLs associated with essential hypertension: GenNet study. Thrombotic genetic risk factors and warfarin pharmacogenetic variants in Sao Miguel's healthy population (Azores). A candidate gene association study of 77 polymorphisms in migraine. Prevalence of genetic thrombophilic polymorphisms in the Sri Lankan population--implications for association study design and clinical genetic testing services. An evaluation of candidate genes of inflammation and thrombosis in relation to the risk of venous thromboembolism: The Women's Genome Health Study. Association of common genetic variations and idiopathic venous thromboembolism. Results from EDITh, a hospital-based case-control study. Clotting factor gene polymorphisms and colorectal cancer risk. Gene panels to help identify subgroups at high and low risk of coronary heart disease among those randomized to antihypertensive treatment: the GenHAT study. Candidate gene study of genetic thrombophilic polymorphisms in pre-eclampsia and recurrent pregnancy loss in Sinhalese women. Placental Abruption Oral Contraceptives, HRT and Risk of VTE

T;T

Significantly increased risk of thrombosis. The homozygous minor allele variant is very rare. Magnitude & Odds ratio is from a 2013 study, based on 116 subjects among cases and 24 controls. See discussion at rs6025. Note: Independent risk for thrombosis was also seen in variants of the PT20210A or Factor 2 SNP at i3002432 (also known as rs1799963

C;T

See discussion at Rs6025. Odds ratio based on 2013 and 2017 studies.

C;C

see info at Rs6025