Emerging evidence from in vitro, animal, and human studies has indicated that ROS/RNS and the activation of redox-sensitive signalling pathways play a crucial role in cancer development
[26–29]. Such antioxidant mechanisms are extremely important, as they represent the direct removal of ROS/RNS, particularly during gliomatous carcinogenesis. To investigate the potential association between SNPs in antioxidant defence genes and the risk of glioma occurrence, we conducted this case–control study. In this study, we observed a statistically significant association between four SNPs (SOD2 V16A, SOD3 T58A, GPX1 -46 C/T, and NOS1 3’-UTR) of antioxidant genes and the risk of glioma occurrence in a Chinese population. Additionally, three SNPs exhibited statistically significant evidence of differential dose–response associations. To the best of our knowledge, this is the first report of an association study between antioxidant gene SNPs and glioma risk in a Chinese population.
SODs are a ubiquitous family and represent the most important line of antioxidant enzyme defence against ROS, particularly the superoxide anion radicals
. SOD enzymes, which catalyse the spontaneous dismutation of the superoxide radical into hydrogen peroxide, are present in all subcellular milieus of the nervous system, including the mitochondrial intermembrane space (SOD1; copper/zinc SOD); the mitochondrial matrix (SOD2; manganese SOD); and the plasma, lymph, and synovial fluids (SOD3; extracellular SOD)
. Superoxide dismutase 2 (SOD2) (also known as manganese superoxide dismutase [MnSOD]) is an essential defender against mitochondrial superoxide radicals.
SOD2 converts the superoxide anion radical into hydrogen peroxide and oxygen within mitochondria and plays a key role in protecting cells from oxidative damage
. In the early stages of carcinogenesis, oxidative stress and relatively low levels of MnSOD result in DNA damage and cell injury
[32–34]. MnSOD plays a critical role in the defence against oxidant-induced injury and apoptosis of rapidly growing cancer cells, and the tumour-suppressive effects of MnSOD have been well established
[12, 14, 35]. Whereas Chung-man et al.
 and Izutani et al.
 previously found increased SOD2 levels in cancer cells, other studies have reported elevated MnSOD expression levels in aggressive cancers compared to benign counterparts, and this increased expression has been proposed to enhance metastasis following cancer progression, possibly through increased expression of matrix metalloproteinases (MMP)
[38, 39], which is one possible mechanism supporting the role of SOD2 in cancer invasiveness and metastatic capacity. The overexpression of SOD2 can also induce increased levels of hydrogen peroxide (H2O2)
[40, 41]. H2O2 is a major intracellular oxidant and induces DNA damage in glioma cells
[42, 43]. Although it might be difficult to determine the precise mechanisms that are most relevant to the pathologies of the patients in this study, the identification of these two possible mechanisms is consistent with our results.
To our knowledge, most epidemiological studies have indicated that SOD2 polymorphisms are linked to clinically significant increases in colon, gastric, lung, breast, and prostate cancers
[16–20]. These polymorphisms have also been linked to the development of meningiomas and glioblastomas
. Here, our results revealed a statistically significant association between SOD2 rs4880 and the risk of glioma. Rajaraman P et al.
 showed an increased risk of acoustic neuroma with the SOD2 (Val16Ala) Ala variant, but no significant association between the C genotype and the risk of glioma was observed. The T-to-C nucleotide polymorphism (rs4880), which converts a valine to an alanine in the mitochondrial targeting sequence at position 16 of the protein (Val16Ala), is considered one of the most interesting polymorphisms in the SOD2 gene. The Val-to-Ala transition alters the secondary structure of the protein, resulting in more efficient transport of SOD2 into the mitochondrial matrix. Thus, the C allele can increase the ability of SOD2 to neutralise superoxide radicals compared to the T allele
[45, 46]. Diffuse invasion into the surrounding brain is a characteristic feature of gliomas, essentially preventing surgical cure, leading to recurrence and representing perhaps the largest obstacle to effective therapy. The invasive nature of glioma cells into the brain parenchyma is intimately linked to the degradation of the extracellular matrix. Activated MMPs are a prerequisite for cancer cell invasion and metastasis. Several lines of evidence have suggested that the overexpression of SOD2 induces a profound increase in the expression of MMP-1
[47–49]. Because the Ala mutant confers a 40% higher MnSOD activity than the Val wild-type form, the increased levels of SOD2 result in increased risk for more invasive glioma activity by inducing MMPs. Our results are consistent with this function of the SOD2 rs4880 in glioma and warrant further investigation. A recent study has indicated that SOD2 rs4880 might significantly modulate the prognosis of breast cancer patients
, implicating SOD2 rs4880 as a potential prognostic biomarker in gliomas.
Our results also indicate a role for SOD3 rs2536512 in the risk of glioma and demonstrated that the SOD3 A genotype correlated with a significantly increased risk of glioma occurrence in a Chinese population. SOD3 was first detected in human plasma, lymph, ascites, and cerebrospinal fluids
. This SNP (rs2536512) results in a threonine-to-alanine conversion that replaces a polar hydrophilic amino acid with an aliphatic hydrophobic amino acid at position 58 of the SOD3 protein, eliminating a PKC delta phosphorylation motif
. Few studies have been performed to examine the association between SOD3 rs699473 and glioma risk or to explore the association between SOD3 rs2536512 and cerebral infarction in women
. Our study has demonstrated an association between the human SOD3 gene and the risk of glioma occurrence. Additionally, we observed statistically significant evidence that carriers of the SOD2 and SOD3 variants exhibit increased glioma dose–response relationships compared with homozygous wild-type subjects (P-trend < 0.001). Confirmation of our findings in alternate populations represents a high priority. The SOD SNP-associated glioma risks observed in our study suggest that the amino acid changes caused by these SNPs might be physiologically significant in the development of cancer.
GPX1 encodes the antioxidant glutathione peroxidase isoform 1 and acts in conjunction with the tripeptide glutathione (GSH), which is present in cells in high (micromolar) concentrations
. Accumulating data link altered or abnormal GPX1 expression with the aetiology of cancer
[54–56]. The additional identification of GPX1 polymorphisms, concordant with several other studies, suggests the involvement of GPX1 variants in the aetiology of glioma
[30, 57]. In these previous studies, the effect sizes occurred at an odds ratio of approximately 1.1; in our study, the rs1800668 SNP in GPX1 was associated with an almost 3.3-fold increased risk when rare homozygotes were compared to common homozygotes. Although the previous studies indicated the same association that was observed in our results, they lacked statistical significance and association. Thus, it is likely that some associations that we have presented here are chance findings. These data only provide evidence that GPX1 rs1800668 contributes to glioma predisposition. Further epidemiologic and functional studies in a larger population are warranted to validate these results.
Nitric oxide (NO), a pleiotropic messenger molecule, is predominantly produced from the precursor L-arginine by neuronal nitric oxide synthase (NOS1) in the central nervous system
[58, 59]. The possible involvement of NOS1 rs2682826 in vital functions has been suggested by several studies. The rs2682826 SNP is located in the 3′-UTR of exon 29 of NOS1 gene. It has been established that the 3′-UTR plays a role in the stability and translational efficiency of the mRNA transcript
. Additionally, the rs2682826 SNP is proximally located to several miRNA-binding sites within the gene’s 3′-UTR. Differences in protein translation might occur depending on the presence of the SNP in the mRNA of this gene
. Further functional analyses are required to clarify these possibilities.
In this population sample, NOS1 rs2682826 might play a protective role in the development of glioma under the dominant model (adjusted OR = 0.61; 95% CI = 0.45–0.82; P-trend = 0.017). Additional evidence substantiating the physiological relevance of the NOS1 rs2682826 polymorphisms was previously revealed by Ibarrola-Villava et al.
, who found that NOS1 rs2682826 is associated with protective effects in malignant melanoma, accounting for a 40% reduction. If confirmed, the evidence presented in this study here would facilitate the identification of individuals who possess the heterozygote or rare homozygote marker of NOS1 rs2682826. These patients would particularly benefit from glioma treatments.
However, the limitations of our study must be addressed. First, these findings cannot be generalised to other populations because our study was specifically conducted using a Chinese population. Second, the number of cases and controls included in this study was relatively small; thus, further studies with larger sample-sizes are needed.
In conclusion, we have demonstrated that the influence of these genetic variations in the oxidative response has a potential regulatory effect on glioma tumourigenesis, and furthermore, we have identified a trend towards an increasing glioma risk associated with an increasing number of unfavourable genotypes that occur in a dose-dependent manner. To our knowledge, this study provides the first epidemiological evidence that supports an association between oxidative response-related genes and glioma risk in a Chinese population. Further studies are warranted to assess the observed effects using a more comprehensive collection of SNPs in oxidative response genes.