Identification of gene modules associated with warfarin dosage by a genome-wide DNA methylation study.

Abstract

To identify warfarin dose-associated DNA methylation changes, we conducted the first genomewide DNA methylation association study. A total of 22 patients who required an extreme warfarin dosage from VKORC1 -1639AA & CYP2C9*1*1 genotype group were enrolled in this study. The Illumina Infinium HumanMethylation450 platform was used to perform genome-scale DNA methylation profiling, identifying differentially methylated CpG sites by a nonparametric test. WGCNA was used to analyze the association between gene modules and extreme warfarin dosage. For a total of 378,313 CpG sites that passed the quality control processes, we identified eight differentially methylated CpG probes (p<0.05) showing altered DNA methylation level (>20%) between two extreme dose groups. Though the WGCNA method we identified two gene modules, Turquoise and Light-cyan, with high methylation level were significantly correlated with high warfarin doses (P-values were 0.036 and 0.022 respectively). Both gene modules exhibited good warfarin dosage prediction performance (77% for the Turquoise module and 79% for the Light-cyan module). This study showed for the first time that DNA methylation level changes are significantly associated with warfarin dosage, providing a novel idea for understanding warfarin dose various and laying the groundwork for further related studies.