Association between polymorphisms in the GSTA4 gene and risk of lung cancer: A case–control study in a Southeastern Chinese population

Abstract

GST Alpha 4 (GSTA4) has an important role in the protection against oxidative stress induced by carcinogens such as tobacco smoke. However, few studies investigated the association between GSTA4 polymorphisms and lung cancer risk. We genotyped three selected GSTA4 SNPs (rs182623 - 1718:T > A, rs3798804 + 5034:G > A and rs316141 + 13984:C > T) in a case-control study of 500 lung cancer patients and 517 cancer-free controls and evaluated the association between these SNPs and risk of lung cancer in this Han Chinese population. We found that there was a significant difference in genotype and allele frequency distributions of GSTA4 -1718 between the cases and the controls (P = 0.006 and P = 0.003, respectively). Compared with the GSTA4 -1718TT genotype, individuals with the TA + AA genotypes had a significantly decreased risk of lung cancer (adjusted OR, 0.63; 95% CI, 0.47-0.84; P = 0.006). Although there were no such statistical differences between the cases and controls at the loci +5034 and +13984, nor for histological types, individuals carrying the genotypes of -1718TA, +5034GG and +13984CT had a significantly decreased lung cancer risk (OR, 0.37; 95% CI, 0.23-0.61; P < 0.0001), especially for those smokers who smoked </=25 pack-years (P < 0.000001). These results need to be confirmed in larger studies with different ethnic groups.

Quantitation of mercapturic acid conjugates of 4-hydroxy-2-nonenal and 4-oxo-2-nonenal metabolites in a smoking cessation study

“…On the other hand, genetic polymorphism of GST may affect gene expression if the mutation is located in the promoter region. Qian et al [37] studied single nucleotide polymorphisms (SNPs) of GSTA4, another GST that accepts HNE as a substrate [38]. Qian et al [37] found that the presence of genotypes TA and AA at locus-1718 of GSTA4 was associated with a 37 % significantly decreased risk of lung cancer compared to the TT genotype.…”

“…Qian et al [37] studied single nucleotide polymorphisms (SNPs) of GSTA4, another GST that accepts HNE as a substrate [38]. Qian et al [37] found that the presence of genotypes TA and AA at locus-1718 of GSTA4 was associated with a 37 % significantly decreased risk of lung cancer compared to the TT genotype. The authors suggested that the TA and AA genotypes, with the SNP in the promoter region, may have increased GSTA4 expression and thus greater capacity to detoxify HNE as compared to the TT genotype.…”

“…Dwivedi et al [39] determined that GSTA4 null mice have higher levels of hepatic HNE after CCl 4 treatment than wild-type mice, indicating reduced HNE conjugation in GSTA4 null mice. In the study by Qian et al [40], the TT genotype had a prevalence of 77 % in lung cancer patients ( n = 500) and 68 % in cancer-free control subjects ( n = 517). The common occurrence of the TT genotype, presumably having reduced GSTA4 expression and reduced capacity to conjugate HNE, may explain the low urinary levels of LPO-MA (< 7 mg/g creatinine) we found in 9 out of 23 smokers.…”

Glutathione S-Transferase Alpha 4 Prevents Dopamine Neurodegeneration in a Rat Alpha-Synuclein Model of Parkinson’s Disease

“…Furthermore, while rat Gsta4 is only 60% homologous with human GSTA4, the two enzymes have similar catalytic affinity to HNE ( 9 ), making it a valuable experimental target. Genetic associations have been made between GSTA4 mutations and risk for certain types of cancer ( 15 , 16 ), but not much is known about the role of GSTA4 in PD. However, HNE has been shown to be significantly elevated in PD brains ( 17 – 19 ), suggesting that GSTA4 is somehow affected and could be a key player in the disease.…”

Naturally Occurring Variation in the Glutathione-S-Transferase 4 Gene Determines Neurodegeneration After Traumatic Brain Injury

“…Thus, certain Gsta4 polymorphisms increase the risk to develop melanoma and hepatocellular and lung cancer (1,28,32). In CNS diseases there are some indications that a Gstm1 null and a Gstm3 polymorphism increase the risk for PD and AD, respectively (23,30).…”