High-resolution SNP and haplotype maps of the human gamma-glutamyl carboxylase gene (GGCX) and association study between polymorphisms in GGCX and the warfarin maintenance dose requirement of the Japanese population

Abstract

Gamma-glutamyl carboxylase (GGCX) plays an important role in blood coagulation through post-translational carboxylation of vitamin K-dependent blood-clotting proteins. This carboxylation process is impaired in the presence of warfarin, a vitamin K antagonist. Recent studies on GGCX have provided insights into association of polymorphisms in this gene, with inter-individual differences in the required warfarin maintenance dose. In order to provide a useful resource for further elucidating this association, we here report a high-resolution single nucleotide polymorphism (SNP) and haplotype maps of an 18-kb genomic region corresponding to the GGCX locus in the Japanese population. Among 41 SNPs, seven insertion/deletion polymorphisms, and a microsatellite polymorphism that we detected by direct sequencing of the DNAs of 96 Japanese individuals who were treated with warfarin, 32 genetic variations have not been reported. Using genotype information from 12 SNPs and the EM algorithm, we estimated haplotypes for this genomic region. Subsequently, we investigated associations of each of these polymorphisms with the warfarin maintenance-dose requirements of 828 Japanese patients, including the 96 patients that were used for DNA sequencing. We found no significant association between the polymorphisms in GGCX and the dose requirement.