VIP Variant in F5
Note: The F5 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations may differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
The Factor V Leiden (FVL, 1691G>A) polymorphism results in an Arg to Gln substitution at position 506 in the Factor V heavy chain. Factor V has a 28 amino acid leader peptide, thus this polymorphism has also been referred to as Arg534Gln in the literature and some databases [Article:3110773]. This amino acid substitution occurs at an important cleavage site and significantly reduces the rate at which factor Va is deactivated by activated protein C (APC). FVL also decreases the APC cofactor activity of factor V in the deactivation of factor VIIIa. The combination of impaired factor Va and VIIIa deactivation results in a prothrombotic state. [Articles:7657663, 7989361, 7876154, 8815575, 15257017, 10194434, 8573079, 16359508, 14976057, 12881304]
The minor allele frequency of FVL reported in HapMap, dbSNP, and other databases is between 0.8%-2.7% in European populations. However, reports in the primary literature show great variability in allele frequency according geographic distribution. FVL is found predominantly in individuals of European descent. Reported allele frequencies are as high as 15% in some areas, with the greatest prevalence in the Eastern Mediterranean and Sweden. FVL is very rare among populations of African, East Asian and Native American descent with reported allele frequencies <1%. In admixed populations (i.e. Hispanic), allele frequencies in some areas are consistent with that of the Europeans. [Articles:16651467, 9109469, 9157591, 11259157, 10936863, 9271712, 9415695, 7475606]
The association between FVL and venous thromboembolism (VTE) is well established. Heterozygotes have at least a two-fold greater risk of deep vein thrombosis, and the risk appears to be additive as the estimates are much higher in homozygotes. [Articles:16651467, 9382368, 7877648, 11529695, 7888671, 10073951, 14996674, 12368166, 16606808] FVL enhances the risk of VTE associated with the use of oral contraceptives and estrogen hormone replacement therapy. Mechanistically, FVL enhances APC resistance induced by oral contraceptives and hormone replacement therapy. [Articles:12869355, 14551147, 12138364, 11703344] Users of oral contraceptives with the FVL mutation have up to a 40-fold increased risk of VTE compared to nonusers without the variant, although the risk estimates vary across studies given the low frequency of exposed cases with the variant. In a meta-analysis of six studies, the pooled odds of VTE with oral contraceptives in FVL carriers was 15.62 (95% confidence interval 8.66-28.15), which is substantially higher than the population risk estimates (odds ratio for VTE in all users versus nonusers 3.10, 95% confidence interval 2.17-4.42). Similarly, individuals receiving oral estrogen hormone replacement therapy with FVL have as much as a 25-fold increased risk of VTE compared to nonusers without the mutation. Transdermal preparations may not carry the same risk. [Articles:9459317, 10943572, 10073976, 11532625, 7968118, 15467059, 16301339, 16113779, 12069454, 12067913, 11886391] Despite these high relative risks, the absolute risks remain low and so testing for FVL is not recommended for all potential oral contraceptive or hormone replacement therapy users, although these should be avoided in women known to be a carrier of FVL. [Article:16595080] FVL does not appear to modify the risk for venous thromboembolism among women with breast cancer receiving tamoxifen [Articles:14512389, 16818854]. Most studies failed to show an association between FVL and arterial thrombosis in the general population. However, a recent meta-analysis of 60 studies, which included over 15,000 cases, demonstrated a significantly greater risk of coronary disease and myocardial infarction in FVL carriers. [Articles:9531249, 8553401, 8581514, 10195931, 10702702, 11406725, 16503463, 7877648, 10666427, 15534175, 14660985, 15947254, 12877676, 9108400, 14574075]. Additionally, the risk of stroke and myocardial infarction is increased in female carriers of FVL that smoke. [Articles:15947254, 12877676, 9108400] Anticoagulation therapy is not currently recommended for individuals with FVL who have no history of thromboembolism. [Articles:12368166, 11958494, 12008938, 16595080, 9462312, 16173967, 11127850]
In animal models, heterozygosity for FVL confers a survival benefit in severe sepsis. [Articles:12869495, 15118524] However, human studies suggest that FVL heterozygotes have similar outcomes in the setting of sepsis and derive similar benefits and adverse events from drotrecogin alfa (recombinant human activated protein C) as noncarriers. [Articles:16444434, 15118525]
| Key Publications: | |
|---|---|
| Drugs / Other Molecules | |
| Diseases | Sepsis 33 34 Thrombosis 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 venous thromboembolism 50 51 52 53 54 55 56 57 58 59 60 |
Appendix
Name: F5:1691G>A (nucleotide reference based on F5 sequence published by Jenny et al. [Article:3110773]
( Factor V Leiden (FVL) )
( Arg506Gln (amino acid position not including leader peptide (28 amino acids)). )
| Coriell Clone containing heterozygous reference allele: | GM16028 |
|---|---|
| Coriell Clone containing homozygous minor allele: | GM14899 |
| Genomic Variant & GenBank ID: | T>C 20009404 on NT_004487 |
|---|---|
| mRNA Variant & GenBank ID: | G>A 1746 on NM_000130(nucleotide position relative to start of 5'UTR), G>A 1691 on M16967.1 |
| Protein Variant & GenBank ID: | Arg>Gln 534 on NP_000121 (amino acid position including leader peptide (28 amino acids)) |
| gp Position : | chr1:167785673(hg18) |
Connected Drugs
| Evidence | Drug |
|---|---|
| drotrecogin alfa | |
| tamoxifen |
Connected Drug Classes
| Evidence | Drug Class |
|---|---|
| VIP Annotation | estrogens |
| VIP Annotation | hormonal contraceptives for systemic use |
Connected Diseases
| Evidence | Disease |
|---|---|
| Sepsis | |
| Thrombosis | |
| venous thromboembolism |
Publications related to rs6025 at chr1:169519049: 79
Cross-References
- UCSC Golden Path:
- chr1:169519049
- dbSNP:
- rs6025
- ALFRED:
- SI001216K
- HapMap:
- rs6025
- Seattle SNP:
- F5-038592
Platform Availability
- Illumina