Cavalli M, Pan G, Nord H, Eriksson N, Wadelius C, Wadelius M
Pharmacogenomics 17 (12) 1305-1314 [2016-08-00; online 2016-02-06]
Warfarin dose requirement is associated with VKORC1 rs9923231, and we studied whether it is a functional variant. We selected variants in linkage disequilibrium with rs9923231 that bind transcription factors in an allele-specific way. Representative haplotypes were cloned or constructed, nuclear protein binding and transcriptional activity were evaluated. rs56314408C>T and rs2032915C>T were detected in a liver enhancer in linkage disequilibrium with rs9923231. The rs56314408-rs2032915 C-C haplotype preferentially bound nuclear proteins and had higher transcriptional activity than T-T and the African-specific T-C. A motif for TFAP2A/C was disrupted by rs56314408T. No difference in transcriptional activity was detected for rs9923231G>A. Our results supported an activating role for rs56314408C, while rs9923231G>A had no evidence of being functional.