What are the genetic changes related to warfarin sensitivity ?
Many genes are involved in the metabolism of warfarin and in determining the drug's effects in the body. Certain common changes (polymorphisms) in the CYP2C9 and VKORC1 genes account for 30 percent of the variation in warfarin metabolism due to genetic factors. Polymorphisms in other genes, some of which have not been identified, have a smaller effect on warfarin metabolism.  The CYP2C9 gene provides instructions for making an enzyme that breaks down compounds including steroids and fatty acids. The CYP2C9 enzyme also breaks down certain drugs, including warfarin. Several CYP2C9 gene polymorphisms can decrease the activity of the CYP2C9 enzyme and slow the body's metabolism of warfarin. As a result, the drug remains active in the body for a longer period of time, leading to warfarin sensitivity.  The VKORC1 gene provides instructions for making a vitamin K epoxide reductase enzyme. The VKORC1 enzyme helps turn on (activate) clotting proteins in the pathway that forms blood clots. Warfarin prevents (inhibits) the action of VKORC1 and slows the activation of clotting proteins and clot formation. Certain VKORC1 gene polymorphisms decrease the amount of functional VKORC1 enzyme available to help activate clotting proteins. Individuals develop warfarin sensitivity because less warfarin is needed to inhibit the VKORC1 enzyme, as there is less functional enzyme that needs to be suppressed.  While changes in specific genes, particularly CYP2C9 and VKORC1, affect how the body reacts to warfarin, many other factors, including gender, age, weight, diet, and other medications, also play a role in the body's interaction with this drug.