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  • 13(S)-HODE Selenium s actions in the body are


    Selenium’s actions in the body are exerted through its incorporation as the amino 13(S)-HODE selenocysteine into 25 selenoproteins thought to exert most of the functions of Se in the body [14]. Nearly all of the well-characterized selenoproteins possess a role in antioxidant function and redox status in the cell [25]. A number of other genes exert effects on bioavailability and action of Se in the cell. Among them, SEPSECS is involved in the regulation of selenoprotein synthesis [26]. SEPHS1 is one of two selenophosphate synthases in mammals; unlike SEPSH2, a known selenoprotein, the function of SEPHS1 has not been determined though it is hypothesized to play a role in cell differentiation and proliferation [27]. Interactions of SPECSECS and SEPHS1 with SEPHS2 play a role in selenocysteine biosynthesis [28]. GCLC and GCLM are subunits of GCL (glutamate cysteine ligase) which is the first rate-limiting enzyme of glutathione biosynthesis [29]. Single-nucleotide polymorphisms (SNP) in selenium pathway genes have been linked to the risk of colorectal, prostate, lung or breast cancers [30] but are poorly studied in glioma. The aim of this study was to investigate the association between toenail Se concentrations and genetic variants in selenoproteins and related genes in relation to glioma risk and survival in a US case-control study. Associations with genetic variants were also investigated in the UK Biobank cohort [31].
    Subjects and methods
    Discussion While other studies have examined the association of other trace elements and glioma [12,38], this study is novel in its consideration of the role of toenail Se levels, as well as the variants involved in selenoprotein metabolism in association with glioma risk and survival. Se has been implicated as having a protective role in colorectal and prostate cancer [39,40], and low Se levels have been associated with neurodegenerative disease [41,42] as well as tumor progression [43]. An in vitro study of Se in human brain tumor cell lines showed growth inhibition and apoptosis in glioma cells treated with Se [44], suggesting that higher levels of pre-diagnostic Se might have a protective role in gliomagenesis or reduce aggressiveness of tumors. However, the present data offered no support for a salutary influence of selenium on either outcome in glioma. The present study offered no support for a role of selenium pathway germline variation in glioma. Several of the members of the selenoprotein family harbor functional variants that affect Se bioavailability and have been associated with susceptibility to specific cancers [45,46]. Among them, SNPs in selenoprotein P thioredoxin reductases 15 kDa, GPx-1, GPx-3, GPx-4, and selenoprotein S were evaluated in the present study with overall null results [45,46]. Several variants in the selenoenzyme pathway linked to colon or rectal cancer in one study [47] were associated with overall risk of glioma (rs6659086) or with nonGBM (rs9637365) in the case-control study; however, they were not validated in the cohort study analysis. Rajaraman et al examined the relationship between the innate immune system and glioma [48], and reported two statistically significant SNPs (at p < 0.01) in SELP. Of these, one SNP (rs3917727) was in linkage disequilibrium (LD) (LD = 0.71) with a SNP (rs3917687) associated with nonGBM glioma in the case-control study (OR = 0.86; 95% CI 0.74, 0.99; p = 0.03). However, the association was not observed in the UKB cohort and may be due to chance. A previous GWAS found a significant association between genetic variants in the selenoprotein TXNRD1 and toenail Se levels [49]. This association could potentially explain the significant risk association observed in the UK Biobank with rs4545635 which is in LD (LD = 0.61) with the GWAS SNP associated with toenail selenium (rs7975161). However, this SNP was not associated with glioma risk in the case-control study analysis. Furthermore, among 480 persons with genotyping data that were included in the toenail risk analyses, we found no association between toenail Se and the GWAS linked SNP (rs4545635) nor any of the SNPs associated with glioma risk in either study (Table 4), overall, or among the 192 controls only, after adjustment for FDR (not shown).