Individual sensitivity to warfarin: Nature or nurture?

We evaluated the relative effects of plasma vitamin K [K] and of CYP2C9 genotype polymorphism on the warfarin sensitivity index: WSI= INR/ warfarin dose (mg/d/m² BSA), in 149 patients at steady state stable anticoagulation (mean INR 2.7±0.6) after accounting for the effect of plasma warfarin levels [W], For CYP2C9*1 (allele frequency 0.84), 2C9*2 (0.06) and 2C9*3 (0.09) warfarin maintenance doses were 6.5±3.2, 5.1±2.4 and 3.5±2.1 mg/d (F=7.0, p<0.004) and [W] were 2.1±0.9, 1.9±1.0, 1.5±0.6 mg/L respectively (F=4.0, p<0.03). WSI increased respectively: 0.9±0.5, 1.1±0.6, 2.2±1.8 (F=9.8, p<0.001) but [K] did not differ between genotypes. On multiple regression: WSI was associated with genotype (partial r²=0.14), [W] (r²=0.12) and age (r²=0.05), multiple r=0.56, p<0.001, but not with [K]. Beyond the effect of steady state [W], individual sensitivity to warfarin, in patients consuming normal diets, is primarily determined by the CYP2C9 *2 and *3 alleles (surrogates for the S/R warfarin enantiomere ratio in plasma) and age, both constitutional factors, but not by vitamin K status, the environmental element.