Genetic Polymorphism of γ-Glutamyl Hydrolase in Chinese Acute Leukemia Children and Identification of a Novel Double Nonsynonymous Mutation

Abstract

γ-Glutamyl hydrolase (GGH) plays a central role in folate metabolism and antifolate action. Polymorphism in the human GGH gene (GGH) was associated with efficacy and side effects of methotrexate for treatment of acute lymphoblastic leukemia (ALL). This study aimed to identify polymorphisms of GGH in Chinese. Seventy-one children with ALL, 25 children with acute myeloid leukemia (AML), and 132 children with nonmalignancy as control were included. Human GGH cDNAs were prepared and analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR)-denaturing gradient gel electrophoresis. The detected variants were further confirmed by DNA sequencing. Novel variant GGH cDNA was cloned, expressed, and characterized. Allelic frequency of GGH 452C→T polymorphism was determined as 9.2% (CT, 11/71; TT, 1/71) in the ALL group, 8.0% (CT, 4/25; TT, 0/25) in the AML group, and 9.1% (TT, 4/132; T/C, 16/132) in the controls, respectively. The total allelic frequency in the Chinese population (9.0%) was higher than those reported in Japanese (5.6%) and African Americans (4.4%), and was similar to Caucasians (10.0%). Association of 452TT+TC with increased rate of hepatotoxicity and mucositis was observed in the ALL patients. Two novel mutations were determined in the coding region of GGH in 2 boys with ALL: one of the mutations was a double nonsynonymous heterozygote (841AG+845AG, K257E/N258S), the other was a nonsynonymous heterozygote (797AG, K242R). The corresponding double-mutant protein showed unchanged enzymatic activity by functional analysis. Allele frequency of GGH C452T polymorphism is determined for the first time among Chinese. A novel double nonsynonymous mutation of GGH was identified in a boy with ALL.

Comparative pharmacogenetic analysis of risk polymorphisms in Caucasian and Vietnamese children with acute lymphoblastic leukemia: prediction of therapeutic outcome?

“…While GGH-452TT genotype was not found in this study, this may well be biased by the moderate sample size. It is indeed a rare variant being only infrequently reported in a Japanese population (one out of 269) [20], in Chinese leukemia children (one in 203) [65], but not found in Mexican paediatric patients with ALL (n = 70) [23]. The prevalence of ITPA-94AC/AA genotypes in Caucasian (15.1%) and Vietnamese (33.9%) children with ALL was in line with previous studies [37,54,58].…”

Interethnic Differences in Single and Haplotype Structures of Folylpolyglutamate Synthase and Gamma-glutamyl Hydrolase Variants and Their Influence on Disease Susceptibility to Acute Lymphoblastic Leukemia in the Indian Population: An Exploratory Study

“…Frequency of the GGH-401'T' allele in the SI population (29.8%) was significantly lower when compared to West Indians (61%), [28] but it was similar to EUR, North Indian, [23] and Thai populations. [10] In the present study, the frequency of GGH-452'T' allele (16.7%) in SI individuals was significantly higher when compared to Dutch, [22] Japanese, [24] Chinese, [25,26] Brazilian, [27] and Mexican populations, [12] but similar to that found in Puerto Rican [21] and North Indian populations [23] [Table 4].…”

“…In the present study, the GGH452'T' allele was not significantly associated with the risk of ALL [Table 2], and our results are in accordance with the previous studies conducted on Mexican [12] and Chinese populations. [25] Furthermore, in the present study, the GGH-401C>T polymorphism was also not associated with the susceptibility to ALL. Our study results are similar to the findings by Koomdee et al in a Thai population, [10] but not in line with a study done on Mexican population where the -401'T' allele was associated with the risk of ALL (P = 0.001).…”

“…Both FPGS rs10106'G' and rs1544105'A' alleles in the SI population (37%) were significantly lower when compared to AFR, AMR, EAS, PJL, and Thai populations, [20] but were similar to EUR and subpopulations of SAS (except PJL) [Table 4]. [21][22][23][24][25][26][27][28][29] The frequency of the FPGS rs10106'G' allele in the SI population was also lower when compared to Puerto Rican, [21] Dutch, [22] and Singapore Chinese populations, [29] whereas rs1544105'A' allele frequency was lower when compared to a Chinese population (65.9%). [11] There was also a significant difference in the distribution of genotype and allele frequencies of GGH variants (GGH-401 (rs3758149) and 452 C>T (rs11545078)) between the SI population and other ethnicities, except for subpopulations of SAS such as BEB, GIH, ITU, PJL, and STU [Table 4].…”

Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL

“…In another case-control study, Chen et al[50] reported that 452 T allele was significantly associated with increasing rate of hepatotoxicity grade ≥2 [OR=…”