Genetic variations and haplotype structures of the glutathione S-transferase genes, GSTT1 and GSTM1, in a Japanese patient population.
Glutathione S-transferases (GSTs) play a vital role in phase II biotransformation of many synthetic chemicals including anticancer drugs. Deletion polymorphisms in GSTT1 and GSTM1 are reportedly associated, albeit controversial, with an increased risk in cancer as well as with altered responses to chemotherapeutic drugs. In this study, to elucidate the haplotype structures of GSTT1 and GSTM1, genetic variations were identified in 194 Japanese cancer patients who received platinum-based chemotherapy. Homozygotes for deletion of GSTT1 (GSTT1(*)0/(*)0 or null) and GSTM1 (GSTM1(*)0/(*)0 or null) were found in 47.4% and 47.9% of the patients, respectively, while 23.2% of the patients had both GSTT1 null and GSTM1 null genotypes. From homozygous (+/+) and heterozygous ((*)0/+) patients bearing GSTT1 and GSTM1 genes, six single nucleotide polymorphisms (SNPs) for GSTT1 and 23 SNPs for GSTM1 were identified. A novel SNP in GSTT1, 226C>A (Arg76Ser), and the known SNP in GSTM1, 519C>G (Asn173Lys, (*)B), were found at frequencies of 0.003 and 0.077, respectively. Using the detected variations, GSTT1 and GSTM1 haplotypes were identified/inferred. Three and six common haplotypes (N> or =10) in GSTT1 and GSTM1, respectively, accounted for most (>95%) inferred haplotypes. This information would be useful in pharmacogenomic studies of xenobiotics including anticancer drugs.
Tatewaki
Naoko
N
National Institute of Health Sciences, Tokyo, Japan.
Maekawa
Keiko
K
Katori
Noriko
N
Kurose
Kouichi
K
Kaniwa
Nahoko
N
Yamamoto
Noboru
N
Kunitoh
Hideo
H
Ohe
Yuichiro
Y
Nokihara
Hiroshi
H
Sekine
Ikuo
I
Tamura
Tomohide
T
Yoshida
Teruhiko
T
Saijo
Nagahiro
N
Saito
Yoshiro
Y
Sawada
Jun-ichi
J
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D001711:Biotransformation; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy; D020641:Polymorphism, Single Nucleotide
D005982:Glutathione Transferase; C413545:glutathione S-transferase T1