A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose
A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose
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DOI：
10.1182/blood-2008-01-134247
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发表时间：
2008-08-15
期刊：
影响因子：
20.3
通讯作者：
Rieder, Mark J.
中科院分区：
文献类型：
--
作者：
Cooper, Gregory M.;Johnson, Julie A.;Rieder, Mark J.
Warranty剂量与维生素K环氧化物还原酶复合物1（VKORC 1）和细胞色素P450 2C 9（CYP 2C 9）基因多态性相关。最近，FDA修订了华法林标签，以提高医生对这些遗传效应的认识。随机临床试验正在进行中，以测试基于基因的剂量算法。因此，确定其他基因中常见的单核苷酸多态性（SNP）是否对华法林剂量有很大影响是很重要的。设计了一项回顾性全基因组关联研究，以确定可以解释大部分剂量变异的多态性。研究了来自华法林索引人群（n = 181）和2个独立重复患者人群（n = 374）的白色患者。在测试的约550，000个多态性中，最显着的独立效应与指标患者中的VKORC 1多态性相关（P = 6.2 x 10（-13））。CYP 2C 9（rs 1057910 CYP 2C 9 *3）和rs 4917639）在中度显著性水平与剂量相关（p类似于10（-4））。来自索引研究的复制多态性（355个SNP）在复制患者组中未显示任何显著影响。我们得出结论，对华法林剂量有较大影响的常见SNP不太可能在CYP 2C 9和VKORC 1基因之外发现。因此，考虑这2个基因的随机临床试验应该产生明确和广泛适用的结果。
Warfarin dosing is correlated with polymorphisms in vitamin K epoxide reductase complex 1 (VKORC1) and the cytochrome P450 2C9 (CYP2C9) genes. Recently, the FDA revised warfarin labeling to raise physician awareness about these genetic effects. Randomized clinical trials are underway to test genetically based dosing algorithms. It is thus important to determine whether common single nucleotide polymorphisms (SNPs) in other gene(s) have a large effect on warfarin dosing. A retrospective genome-wide association study was designed to identify polymorphisms that could explain a large fraction of the dose variance. White patients from an index warfarin population (n = 181) and 2 independent replication patient populations (n = 374) were studied. From the approximately 550 000 polymorphisms tested, the most significant independent effect was associated with VKORC1 polymorphisms (P = 6.2 x 10(-13)) in the index patients. CYP2C9 (rs1057910 CYP2C9*3) and rs4917639) was associated with dose at moderate significance levels (p similar to 10(-4)). Replication polymorphisms (355 SNPs) from the index study did not show any significant effects in the replication patient sets. We conclude that common SNPs with large effects on warfarin dose are unlikely to be discovered outside of the CYP2C9 and VKORC1 genes. Randomized clinical trials that account for these 2 genes should therefore produce results that are definitive and broadly applicable.