After adjustment for multiple comparisons, there were no significant associations between any of the 142 SNPs involved in oxidative stress pathways and either glioma or meningioma. This remained true even when restricting the analyses to patients with GBM, the most common and aggressive sub-type of glioma. However, polymorphisms in the RAC2 and GPX1 genes were found to significantly modify the association between cumulative lead exposure and risk of GBM even after adjustment for multiple comparisons. In addition to a polymorphism in the XDH gene, two highly correlated polymorphisms in the GPX1 gene were also found to significantly modify the association between cumulative lead exposure and risk of meningioma.
Among studies that specifically examined glioma or looked at all brain tumor types (of which glioma was typically the most frequent), results have been mixed (5
). We did not observe a statistically significant association between cumulative lead exposure and risk of glioma or GBM. However, we did observe statistically significant evidence of differential lead-GBM dose-response associations among carriers and non-carriers of three SNPs.
Given the rarity of meningioma, not many studies have evaluated the association of these tumors with lead exposure. Nonetheless, three previous studies, as well as a previously published analysis of these data, have demonstrated positive associations between lead exposure and risk of meningioma (6
). Consistent with our previous analysis that used a slightly different method of exposure categorization, we observed a statistically significant association between cumulative lead exposure and risk of meningioma.
RAC2 is an enzyme involved in regulating the production of reactive oxygen species (22
). While over-expression and mutations of RAC2
has been previously reported in brain tumors (23
), the results of a recent study found RAC2
to be rarely mutated in gliomas (22
). In that study, all six coding exons of RAC2
were sequenced among 78 gliomas (including 18 GBMs), and the rs2239774 polymorphism was most frequently observed (20%), but there was no association with any particular subtype of glioma (22
). Further work is required to determine the impact of this polymorphism and lead exposure on RAC2 activity.
GPX1 is a ubiquitously expressed enzyme that protects tissues from oxidative damage (25
). While the two GPX1
polymorphisms that we examined in our study may be linked with other SNPs or gene regions that are in fact causing the observed effect modification, GPX1
rs1050450 has been shown to have a functional impact on GPX1 enzyme activity (8
), and, as such, may be the causal variant. The variant GPX1 enzyme is less responsive to stimulation and may promote the development of cancer because of reduced levels of protection against oxidative damage from ROS that may be generated by lead. Lead has also been shown to decrease the activity of GPX1 by binding to the enzyme (26
). This action, coupled with the decreased responsiveness of the GPX1 variant enzyme to selenium, may also result in reduced levels of protection against oxidative damage.
We also observed effect modification of the relationship between lead and meningioma by the rs7574920 polymorphism of the XDH
gene. XDH is converted to xanthine oxidase, which is known to generate ROS in mammalian cells (27
). In hamster cell lines, exposure to lead has been shown to stimulate the activity of xanthine oxidase (28
). Thus, the rs7574920 polymorphism in XDH
(or another SNP or region that is in linkage disequilibrium) may make the xanthine oxidase enzyme less responsive to stimulation by lead, resulting in the reduced production ROS, and thus less cellular damage.
Our findings for GBM and meningioma persisted after controlling for multiple comparisons. Our analyses with exclusion of specific subsets of controls one at time suggested that a systematic bias in our results due to the use of hospital controls was unlikely. Nonetheless, given the small numbers of GBM and meningioma cases and the exploratory nature of the study, chance may explain our results.
Use of a biomarker for cumulative lead exposure such as bone lead measurements rather than exposure assessment based on self-report would have been ideal. However, evaluation of the association between lead exposure and brain tumors was not the primary objective of this study when it was initiated, and, as such, biomarker data for lead exposure were not collected.
While the results of our study provide evidence that lead may exert carcinogenic effects through mechanisms related to oxidative damage, the results must be confirmed in other populations. Pooled analyses from several epidemiologic studies would be helpful to allow for more conclusive examinations of potential effect modification of the lead-GBM and lead-meningioma associations by specific genotypes. However, this will require concerted efforts to obtain high quality occupational lead exposure data. Future studies may consider evaluating markers of oxidative stress in lead exposed populations to evaluate the role of oxidative stress as a mechanism for lead-induced carcinogenicity, though it may be difficult to determine which biomarkers are most relevant.