Could MicroRNA polymorphisms influence warfarin dosing? A pharmacogenetics study on mir133 genes.

MicroRNAs are small single stranded molecules that play a crucial role in regulation of physiological and pathological processes. Recent studies showed that VKORC1 gene contains an highly evolutionary conserved binding site for mir-133. Moreover, in human hepatocytes mir-133 is constitutively co-expressed with VKORC1. Since VKORC1 protein is the target of warfarin treatment, the aim of this study was to verify if genetic variations in MIR133A1, MIR133A2 and MIR133B could contribute to warfarin dose variability. By direct sequencing, we identified 4 SNPs in MIR133A2 gene and 1 SNP in MIR133B gene. Three SNPs in MIR133A2 were in complete linkage disequilibrium and correlated with warfarin dose: indeed, for each SNP, patients carrying the GA or AA genotype required a MWWD significantly higher than the wildtype genotype (P=0.019). We also inferred the haplotypes in MIR133A2 gene. The GC haplotype required a MWWD significantly lower than AT haplotype (P=0.012). The multiple linear regression analysis confirmed that rs45547937 (as tag SNP) in MIR133A2 could be involved in warfarin dosing variability, (P=0.016). These results seem to suggest that also polymorphisms in miRNA precursors may potentially affects drug response variability.