Instituto Valenciano de Microbiología

Masía El Romeral
Ctra. de Bétera a San Antonio Km. 0.3
46117 Bétera (Valencia)
Phone. 96 169 17 02
Fax 96 169 16 37
CIF B-96337217


Warfarin sensitivity; Coumarin sensitivity - CYP2C9, VKORC1, CYP4F2, F9 and GGCX genes

Sensitivity to warfarin, also known as coumarin sensitivity, is an alteration in which individuals have a low tolerance to warfarin. Warfarin is an anticoagulant that is often prescribed to prevent the formation of thrombosis in people with valvular heart disease, with atrial fibrillation, with a history of myocardial infarction, stroke, or deep vein thrombosis. Many people with warfarin sensitivity require more time than usual to metabolize warfarin, so the drug stays in their body longer than usual and requires them to be given lower doses. These individuals are classified as "slow metabolizers" of warfarin. Other people with sensitivity to warfarin do not need as much medication to prevent thrombus formation because their thrombus formation process is slower than average and can be inhibited by low doses of warfarin. If people who are sensitive to warfarin take the average (or more) dose of warfarin, they are at risk for an overdose, which can lead to bleeding in the brain, gastrointestinal tract, or other tissues, which can lead to serious health problems or death. The sensitivity to warfarin does not seem to cause health problems other than those related to the pharmacological treatment warfarin.

In most cases, this process is due to polymorphisms in the CYP2C9 gene (cytochrome P450 family 2 subfamily C member 9) and VKORC1 gene (vitamin K epoxide reductase complex subunit 1). Polymorphisms in other genes such as the CYP4F2 gene (cytochrome P450 family 4 subfamily F member 2), F9 (coagulation factor IX) and GGCX (gamma-glutamyl carboxylase) have a minor effect on the metabolism of warfarin. In other cases, the genetic cause related to the disease is unknown. Although genetic changes affect the way the body reacts to warfarin, many other factors, including sex, age, weight, diet, and other medications, also play a role in the body's interaction with this drug.

The CYP2C9 gene (cytochrome P450 family 2 subfamily C member 9), located on the long arm of chromosome 10 (10q23.33), encodes an enzyme found in the endoplasmic reticulum. The CYP2C9 enzyme metabolizes compounds that include the steroid hormones and fatty acids. The CYP2C9 enzyme also plays an important role in the breakdown of warfarin, which fluidifies the blood and prevents the formation of blood clots. This enzyme also helps in the metabolism of other drugs such as ibuprofen.

Certain polymorphisms in the CYP2C9 gene, decrease the activity of the enzyme CYP2C9 causing an increase in sensitivity to warfarin. The altered enzyme slows the metabolism of warfarin, allowing the drug to remain active in the body for a longer period of time. The two most common CYP2C9 gene polymorphisms in individuals of European descent change the amino acids in the CYP2C9 enzyme. The first, known as CYP2C9*2, substitutes the amino acid arginine for the amino acid cysteine ​​at position 144, (Arg144Cys or R144C), which causes a decrease in the metabolism of warfarin to such a degree that the prescription doses are reduced by 1/3 in people with this variation. The second polymorphism, known as CYP2C9*3, replaces the amino acid isoleucine with the amino acid leucine at position 359, (Ile359Leu or I359L). In people with this polymorphism, the prescribed doses are usually reduced by a fifth. In rare cases in which individuals have both the CYP2C9*2 polymorphism and the CYP2C9*3 polymorphism, the enzyme activity is severely diminished and the metabolism of warfarin is very slow. In individuals of African descent, the four most frequent CYP2C9 polymorphisms are CYP2C9*5, CYP2C9*6, CYP2C9*8 and CYP2C9*11. These polymorphisms result in a decrease in the metabolism of warfarin that would require a reduction in prescription doses between one-third and one-sixth.

The VKORC1 gene (vitamin K epoxide reductase complex subunit 1), located on the short arm of chromosome 16 (16p11.2), encodes a subunit of the epoxide reductase complex of vitamin K (VKOR). The enzyme complex VKOR is constituted mainly in the liver and extends through the membrane of the endoplasmic reticulum. This complex converts a form of vitamin K into a different form of vitamin K that aids in the activation of coagulant proteins. Multiple polymorphisms of the VKORC1 gene have been associated with warfarin sensitivity. The most common polymorphism, known as VKORC1A, replaces the guanine nucleotide with the nucleotide adenine (1639G>A), which results in a reduction in the amount of coded subunit. As a result, the amount of VKOR complex that is available to convert vitamin K into a form that can help activate the coagulation proteins is reduced. Due to the decrease in the amount of VKOR complex, less warfarin is needed to inhibit the actions of the complex, which results in the sensitivity to warfarin.

The polymorphisms associated with this disease are inherited with an autosomal dominant pattern, which means that one copy of the altered gene in each cell is sufficient to express the sensitivity to warfarin. However, different polymorphisms affect the activity of warfarin to varying degrees. In addition, people who have more than one polymorphism in a gene or polymorphisms in several genes associated with warfarin have a lower tolerance to the effects of drugs or require more time to remove the drug from their body.

Tests performed in IVAMI: in IVAMI we performed the detection of mutations associated with the PCR, amplification of the exons of the CYP2C9, VKORC1, CYP4F2, F9 and GGCX genes, respectively, and their subsequent sequencing.

Recommended samples: blood drawn with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).