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.
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.
Cha
Pei-Chieng
PC
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
Mushiroda
Taisei
T
Laboratory for Pharmacogenetics, RIKEN SNP Research Center, Tokyo, Japan.
Takahashi
Atsushi
A
Laboratory of Statistical Analysis, RIKEN SNP Research Center, Tokyo, Japan.
Saito
Shigeru
S
Tokushukai Hospital Group, Tokyo, Japan.
Shimomura
Hideki
H
Tokushukai Hospital Group, Tokyo, Japan.
Suzuki
Takao
T
Tokushukai Hospital Group, Tokyo, Japan.
Kamatani
Naoyuki
N
Laboratory of Statistical Analysis, RIKEN SNP Research Center, Tokyo, Japan.
Nakamura
Yusuke
Y
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan. yusuke@ims.u-tokyo.ac.jp.|Laboratory for Pharmacogenetics, RIKEN SNP Research Center, Tokyo, Japan. yusuke@ims.u-tokyo.ac.jp.
D000925:Anticoagulants / Q000008:administration & dosage*; D044466:Asian People / Q000235:genetics; D001777:Blood Coagulation / Q000187:drug effects / Q000235:genetics*; D019735:Carbon-Carbon Ligases / Q000235:genetics*; D002874:Chromosome Mapping; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D014859:Warfarin / Q000008:administration & dosage*