Abstract
IntroductionGlutathione S-transferase (GST) gene deletion or polymorphic sequence variations lead to decreased enzyme activity that influences susceptibility and response to chemotherapy in acute lymphoblastic leukemia (ALL). This case–control study investigated the association of GST gene polymorphisms with the etiology and therapeutic outcome of B-ALL among Kashmiri population.MethodsA total of 300 individuals including 150 newly diagnosed B-ALL patients and an equal number of age and gender matched controls were genotyped for five GST gene polymorphisms by polymerase chain reaction–restriction fragment length polymorphism technique (PCR-RFLP) and multiplex PCR techniques.ResultsHigher frequency of GSTT1 null, GSTO2-AG, and GSTO2-GG genotypes was observed in ALL cases compared to controls that associated significantly with ALL risk (GSTT1 null: OR = 2.93, p = 0.0001; GSTO2-AG: OR = 2.58, p = 0.01; GSTO2-GG: OR = 3.13, p = 0.01). GSTM1, GSTP1, and GSTO1 SNPs showed no significant association (p > 0.05). Combined genotype analysis revealed significant association of GSTT1 null/GSTM1 null (OR = 4.11, p = 0.011) and GSTT1 null/GSTP1-AG (OR = 4.93, p = 0.0003) with B-ALL susceptibility. Haplotype analysis of rs4925 and rs156697 revealed that carriers of CG haplotype had increased risk of B-ALL (p = 0.04). Kaplan–Meier plots revealed significantly inferior 3-year disease-free survival for GSTO2-GG carriers (p = 0.002). Multivariate analysis confirmed GSTO2-GG as an independent poor prognostic factor for DFS (HR = 4.5, p = 0.034). Among combined genotypes, only GSTT1 null/GSTP1-AG associated significantly with poorer DFS rates (p = 0.032).ConclusionThis study demonstrated that GSTT1 null individually or in combination with GSTM1null and GSTP1-AG genotypes associated with increased B-ALL risk. Also, rs156697 variant genotypes (AG and GG) associated with B-ALL, whereas the GG genotype of rs156697 influenced the treatment outcome.
Highlights
Glutathione S-transferase (GST) gene deletion or polymorphic sequence variations lead to decreased enzyme activity that influences susceptibility and response to chemotherapy in acute lymphoblastic leukemia (ALL)
The present study successfully genotyped 150 B-Acute Lymphocytic Leukemia (B-ALL) patients comprising 92 (61%) males and 58 (39%) females with 126 (84%) cases from the rural and 24 (16%) from the urban dwelling having a median age of 16 years along with 150 age [median 17 years] and gender matched, leukemia free, healthy control subjects for GSTT1, GSTM1, GSTP1, GSTO1, and GSTO2 SNPs
A significantly higher frequency of GSTT1null genotype 40% was observed in ALL cases compared to 16.0% in healthy controls that associated with increased B-ALL risk (OR = 2.93, 95% confidence interval (CI) = 1.55–5.91, p = 0.0001) whereas the frequency of GSTM1null genotype was 29% in cases compared to 37.3% in controls and showed no significant difference in distribution between the two groups (p > 0.05)
Summary
Glutathione S-transferase (GST) gene deletion or polymorphic sequence variations lead to decreased enzyme activity that influences susceptibility and response to chemotherapy in acute lymphoblastic leukemia (ALL). This case–control study investigated the association of GST gene polymorphisms with the etiology and therapeutic outcome of B-ALL among Kashmiri population. Genetic and pharmacogenomic studies have suggested that genetic polymorphisms in genes encoding xenobiotic metabolizing enzymes involved in detoxification of carcinogens and drugs modify an individual susceptibility to ALL as well as response to treatment [6,7,8]
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