Pharmacogenetic potential

Pharmacogenetics may help doctors provide patients with the right dose of warfarin.

Warfarin is a blood thinner. It was originally developed as a rat poison - its blood-thinning properties were discovered in the 1950s after a US navy recruit took a massive dose in an unsuccessful suicide attempt.

Although now widely used, doctors have to be careful with prescriptions. With too low a dose, it has no effect; at too high a dose, a patient is at risk of bleeding. Several factors affect the dose a patient needs, including genetic make up.

Warfarin illustrates some of the challenges facing pharmacogenetics. Many studies have searched for the genetic factors influencing responses to the drug. They fall into two main categories:

• those affecting metabolism of the drug (CYP genes); the key cytochrome P450 gene is CYP2C9.
• those involved in its mode of action.

Warfarin interferes with an enzyme in the biochemical pathway of blood clotting. Variation in the gene coding for this enzyme (known as VKORC1) has a significant effect on sensitivity to warfarin. Genes coding for other factors in the pathway were candidates for other pharmacogenetic effects, but their influence seems to be small.

However, although much is known about warfarin, it is still difficult to use this information clinically. Not all the factors affecting the response to warfarin have been identified, and testing for those with the greatest effect - CYP2C9 and VKORC1 - is not yet thought to be worthwhile.

Ideally, doctors need a handy algorithm, or equation, into which they can put relevant information - age, weight, CYP2C9 status etc. - and which would recommend a suitable dose. At the moment, doctors rely on their clinical judgement, generally starting at a low dose and working up.