NEW YORK (Reuters Health) - Results of a study conducted in Japan suggest that the large inter-patient variability in the anticoagulant response to warfarin is attributable to genetic variation not only in CYP2C9, which is well known, but also to several vitamin K-dependent protein gene polymorphisms.
Based on their studies, reported in the April 1st issue of the journal Blood, Dr. Ichiro Ieiri and colleagues from Tottori University in Yonago, suggest that combined genotyping of CYP2C9 and key vitamin K-dependent protein genes might be useful in predicting anticoagulant responses.
Previous studies have shown that certain variants in the CYP2C9 gene are associated with large interindividual differences in the response to warfarin therapy.
“But the frequencies of known CYP2C9 variants (e.g., CYP2C9*3) are low, roughly 2% in Japanese and African-Americans and roughly 8% in Caucasians, Dr. Ieiri pointed out in comments to Reuters Health. “Thus, large inter-patient variability, which is routinely observed in clinical settings, can not be predicted or explained by only this determinant.”
Dr. Ieiri and associates investigated the contribution of variants in seven vitamin K-dependent coagulation “genes of interest” to interpatient variability in warfarin response in 45 patients. They looked at the genes for factors II, VII, IX, and X; proteins S and C; and gamma-glutamyl carboxylase (GGC) as well as CYP2C9.
Multiple regression analysis showed that warfarin sensitivity was independently associated with the following polymorphisms: -402G>A of the factor VII gene, 165Thr>Met of the factor II gene, (37-bp repeat)n of the GGC gene, and CYP2C9*3 in cytochrome 450.
“These four gene variants accounted for 50% of the variance of warfarin sensitivity,” Dr. Ieiri told Reuters Health.
“The possible clinical implication is that using individual genetic information we can predict individual warfarin dose-response relationship with over 50% accuracy in Caucasian patients, and with approximately 50% accuracy in Japanese patients,” Dr. Ieiri said.
“Thus, individual genotyping results plus patient’s non-genetic backgrounds (e.g., age) can make warfarin therapy more effective and safe,” he added.
Dr. Bruce Furie of Harvard Medical School in Boston agrees, adding in an editorial that, with this paper, “we finally begin to get to the molecular basis of warfarin sensitivity.”
Source: Blood 2004;103;2437,2630-2635. [ Google search on this article ]
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