Department of Medicine, Washington University in St Louis, St Louis, Missouri, USA.
Clin Pharmacol Ther. 2010 Apr;87(4):445-51. doi: 10.1038/clpt.2009.291. Epub 2010 Mar 3.
Warfarin demonstrates a wide interindividual variability in response that is mediated partly by variants in cytochrome P450 2C9 (CYP2C9) and vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1). It is not known whether variants in calumenin (CALU) (vitamin K reductase regulator) have an influence on warfarin dose requirements. We resequenced CALU regions in a discovery cohort of dose outliers: patients with high (>90th percentile, n = 55) or low (<10th percentile, n = 53) warfarin dose requirements (after accounting for known genetic and nongenetic variables). One CALU variant, rs339097, was associated with high doses (P = 0.01). We validated this variant as a predictor of higher warfarin doses in two replication cohorts: (i) 496 patients of mixed ethnicity and (ii) 194 African-American patients. The G allele of rs339097 (the allele frequency was 0.14 in African Americans and 0.002 in Caucasians) was associated with the requirement for a 14.5% (SD +/- 7%) higher therapeutic dose (P = 0.03) in the first replication cohort and a higher-than-predicted dose in the second replication cohort (allele frequency 0.14, one-sided P = 0.03). CALU rs339097 A>G is associated with higher warfarin dose requirements, independent of known genetic and nongenetic predictors of warfarin dose in African Americans.
华法林在个体间的反应存在广泛的变异性，这种变异性部分由细胞色素 P450 2C9（CYP2C9）和维生素 K 2,3-环氧化物还原酶复合物亚基 1（VKORC1）的变异所介导。目前尚不清楚钙网蛋白（CALU）（维生素 K 还原酶调节剂）的变异是否会影响华法林的剂量需求。我们在一个剂量异常的发现队列中对 CALU 区域进行了重新测序：高剂量（>第 90 百分位数，n = 55）或低剂量（<第 10 百分位数，n = 53）要求的患者（在考虑了已知的遗传和非遗传变量之后）。一个 CALU 变异 rs339097 与高剂量相关（P = 0.01）。我们在两个复制队列中验证了该变体作为更高华法林剂量的预测因子：（i）混合种族的 496 名患者和（ii）194 名非裔美国人患者。rs339097 的 G 等位基因（等位基因频率在非裔美国人中为 0.14，在白种人中为 0.002）与第一个复制队列中需要 14.5%（SD +/- 7%）更高的治疗剂量（P = 0.03）和第二个复制队列中高于预测剂量相关（等位基因频率 0.14，单侧 P = 0.03）。CALU rs339097 A>G 与更高的华法林剂量需求相关，独立于非裔美国人中已知的华法林剂量遗传和非遗传预测因子。
