Prothrombin G20210A

Prothrombin G20210A
Classification and external resources
OMIM 176930#0009
DiseasesDB 32790

Prothrombin G20210A (also the prothrombin 20210 mutation, the factor II mutation, or the prothrombin mutation) is a genetic variant that approximately doubles or triples the risk of forming blood clots in the veins. The variant is commonly associated with the disease venous thromboembolism (VTE), which includes both deep vein thrombosis and pulmonary embolism. Most carriers, though, never develop VTE in their lifetime.[1]

Prothrombin G20210A was identified in the 1990s, is almost exclusively present in Caucasians,[1] and is estimated to have originated in that population slightly over 20,000 years ago.[2] About 2 to 3% of Caucasians carry the variant,[3] and it confers a 2- to 3-fold higher risk of VTE. Deficiencies in the anticoagulants Protein C and Protein S give a higher risk (5- to 10-fold).[1] Behind non-O blood type[4] and factor V Leiden, prothrombin G20210A is one of the most common genetic risk factors for VTE.[5]

The polymorphism is located in a noncoding region of the prothrombin gene (3' untranslated region nucleotide 20210[lower-alpha 1]), replacing guanine with adenine.[5][7] The position is at or near where the pre-mRNA will have the poly-A tail attached.[7] The variant causes elevated plasma prothrombin levels (hyperprothrombinemia),[5] possibly due to increased pre-mRNA stability.[7] Prothrombin is the precursor to thrombin, which plays a key role in causing blood to clot (blood coagulation). G20120A can thus contribute to a state of hypercoagulability, but not particularly with arterial thrombosis.[5] A 2006 meta-analysis showed only a 1.3-fold increased risk for coronary disease.[8]

Heterozygous carriers who take oral contraceptives are at a 15-fold increased risk of VTE,[3] while carriers also heterozygous with factor V Leiden have an approximate 20-fold higher risk.[1] In a recommendation statement on VTE, genetic testing for G20210A in adults that developed unprovoked VTE[lower-alpha 2] was disadvised, as was testing in asymptomatic family members related to G20210A carriers who developed VTE.[9] In those who develop VTE, the results of thrombophilia tests (wherein the variant can be detected) rarely play a role in the length of treatment.[10]

Notes

  1. ↑ Specifically, position 20210 refers to the nucleotide on the sense strand downstream from the DNA that codes for the start codon (ATG, positions 1 to 3).[6]
  2. ↑ Provoked VTE is triggered by situations such as surgery, trauma, cancer, or immobility.

References

  1. ↑ 1.0 1.1 1.2 1.3 Rosendaal FR, Reitsma PH (July 2009). "Genetics of VT". J. Thromb. Haemost. 7 Suppl 1: 301–4. doi:10.1111/j.1538-7836.2009.03394.x. PMID 19630821.
  2. ↑ Coagulation factor II; F2: .0009 thrombosis, susceptibility to OMIM. Accessed January 23, 2012.
  3. ↑ 3.0 3.1 Rosendaal FR (2005). "Venous thrombosis: the role of genes, environment, and behavior". Hematology Am. Soc. Hematol. Educ. Program 2005 (1): 1–12. doi:10.1182/asheducation-2005.1.1. PMID 16304352.
  4. ↑ Reitsma PH, Versteeg HH, Middeldorp S (2012). "Mechanistic view of risk factors for venous thromboembolism". Arterioscler Thromb Vasc Biol 32 (3): 563–8. doi:10.1161/ATVBAHA.111.242818. PMID 22345594.
  5. ↑ 5.0 5.1 5.2 5.3 Martinelli I, Bucciarelli P, Mannucci PM (2010). "Thrombotic risk factors: basic pathophysiology". Crit Care Med 38 (2 Suppl): S3–9. doi:10.1097/CCM.0b013e3181c9cbd9. PMID 20083911.
  6. ↑ Degen SJ, Davie EW (1987). "Nucleotide sequence of the gene for human prothrombin". Biochemistry 26 (19): 6165–77. doi:10.1021/bi00393a033. PMID 2825773.
  7. ↑ 7.0 7.1 7.2 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM (1996). "A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis". Blood 88 (10): 3698–703. PMID 8916933.
  8. ↑ Ye Z, Liu EH, Higgins JP, Keavney BD, Lowe GD, Collins R et al. (2006). "Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls". Lancet 367 (9511): 651–8. doi:10.1016/S0140-6736(06)68263-9. PMID 16503463.
  9. ↑ Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2011). "Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members". Genet Med 13 (1): 67–76. doi:10.1097/GIM.0b013e3181fbe46f. PMID 21150787.
  10. ↑ Baglin T (2012). "Inherited and acquired risk factors for venous thromboembolism". Semin Respir Crit Care Med 33 (2): 127–37. doi:10.1055/s-0032-1311791. PMID 22648484.