A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose

Abstract

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 approximately 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.

Figure 1

Genome-wide P values for warfarin dose association in the index population. All P values shown are for univariate effects using an additive genetic model. Chromosomes are numbered on the x-axis. Polymorphisms within 500 kb of VKORC1 and CYP2C9 are shown in red and blue, respectively. Genome-wide significance was set at the P value 10⁻⁷ (black line), and polymorphisms with P values less than 10⁻⁴ (brown line) were selected for replication, among others (see “Statistical analysis”).