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BLOODY GENES

Warfarin is a commonly used anticoagulant. The dose of warfarin is carefully adjusted to individual requirements using a standardised induction regimen. Certain patients require lower doses than others to maintain their anti-coagulant status.

A report in the Lancet (353:717-719, 1999) suggested an association between polymorphism in cytochrome P450 CYP 2C9 with dose requirements for warfarin. Part of the data reported are shown in Table 1 below:

Table 1

Genotype

Low-Dose Group (n=36)

Random Clinic Group (n=52)

CYP 2C9*1/*1

7 32

CYP 2C9*1/*2

12 9

CYP 2C9*1/*3

10 10

CYP 2C9*2/*3

5 0

CYP 2C9*2/*2

2 1

CYP 2C9*3/*3

0 0

Note: The wild type allele is CYP 2C9*1. Point mutations results in the two allelic variants CYP 2C9*2 where cysteine substitutes for arginine at amino acid 144 and CYP 2C9*3 where leucine substitutes for isoleucine at residue 359.

 

The investigators also found that bleeding episodes (both minor and major) were significantly different in the two groups :

Table 2

Bleeding Episodes

Low-Dose Group

Random-Clinic Group

Minor (% per person-years)

5.27

1.93

Major (% per person-years)

8.28

2.25

 

Comments:

This problem used data from a study to get students to explore some fundamental concepts in pharmacology: pharmacogenetics, the biotransformation of drugs (specifically the role of CYPs), the adverse effects of drugs and hepatic function. Further many groups studied in fair detail the mechanism of action of warfarin and the clotting cascade.


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