Based on the accumulation of evidence that alterations in immune system may contribute to the etiology of brain tumors, we have conducted a detailed association study of adult glioma and common tagging SNPs in 148 innate immune genes and their surrounding regions(8
). In our pooled analysis of two independent case-control studies, we identified three genetic regions of particular interest within two innate immune pathways: SELP
(integrins/cell surface receptors), and SOD1
(oxidative response). In an analysis restricted to glioblastoma, the most common and aggressive tumor subtype, SELP
was again implicated, as were three additional genetic regions: DEFB126/DEFB127, LY96
(pattern recognition and antimicrobials), and SERPINI1
(response genes and tissue factors).
gene exhibited the most consistent association with risk of overall glioma and glioblastoma in our analyses. In fact, the only SNP that was significantly associated with risk of GBM in both NCI and NIOSH studies was an intronic SNP (rs2236868) in the SELP
gene. We are not aware of published epidemiological studies that have evaluated SELP
polymorphisms in this gene in relation to risk of any cancer, including glioma, but there are several reports in which polymorphisms in this gene have been associated with increased risk of premature coronary heart disease (33
), myocardial infarction (34
), childhood-onset systemic lupus (35
), and decreased risk of cognitive deficit following cardiac surgery (36
), potentially underscoring the importance of SELP
polymorphisms in chronic inflammatory conditions. SELP
codes for the membrane glycoprotein P-selectin, an endothelial cell adhesion molecule which plays an important role in inflammatory responses in normal tissues (including the brain) by facilitating the recruitment, transendothelial migration and proliferation of inflammatory cells in the extravascular compartment. In addition to SELP
, the ALOX5
gene from the pathway of integrins, adhesion and related molecules was associated with risk of overall glioma. The involvement of this pathway in pathogenesis of glioma is plausible biologically in the view of the high migratory and invasive potential of glioma cells (37
Our data also suggest a role for genetic variation in oxidative pathway (SOD1
). Mutations in the SOD1
gene have been commonly reported in individuals with amyotrophic lateral sclerosis, a severe neurodegenerative disease (38
). In addition, the SOD1
gene was found to be overexpressed in glial cell lines and contribute to their radioresistance (40
), suggesting a potential role in the biology of glioma.
Analyses restricted to GBM revealed several additional genetic regions of interest in two pathways: DEFB126/DEFB127, LY96
(pattern recognition and antimicrobials) and SERPINI1
(response genes and tissue factors). While this might be due, to some extent, to chance variation with a smaller sample size, it is also possible that restricting to a more homogeneous set of tumors yielded information specific to the etiology of these aggressive tumors. Interestingly, the SERPINI1
gene that encodes neuroserpin is predominantly expressed in the brain and inhibits tissue type plasminogen-activator(41
); also, mutations in SERPINI1
have been associated with early familial encephalopathy(42
). Taken together this may point to a yet unknown role of SERPINI1
in the development of glioblastoma. At present, there appears to be no published evidence on whether the SNPs in DEFB126/DEFB127
genes are associated with risk of other cancers, inflammatory conditions or CNS disorders.
As with all studies, our results are subject to some caveats. Given that the SNPs were chosen as tagging markers for the genetic region and not based on known function, the observed associations could be due to linkage disequilibrium with the true unobserved causal SNPs. Because the median coverage for the genetic regions was 59% (range 7-100%), it is also possible that additional loci could be associated with risk for glioma. While our top associations were consistent in magnitude and direction in two independent studies, these did not withstand adjustment for multiple comparions, and replication of these results is required in order to rule out the possibility of chance findings (43
). We have assembled a large pooled study of adult glioma that had approximately 80% power to detect strong effects (OR ≥ 2) for common alleles (MAF about 20%) after taking multiple comparisons into account. We had limited statistical power to detect modest associations (OR ≤ 1.5), associations with less common alleles, and risks for specific glioma subtypes. We attempted to quantify possible survival bias in the SNP results due to differences in participation rates for blood sampling (41% of all NIOSH cases compared to 88% of NCI cases) by conducting stratified analyses for individuals based on time interval between diagnosis and blood draw. We found that results for the key findings, when restricted to those with a shorter interval between diagnosis and blood draw, were similar to the pooled findings. This indicates that our main findings are unlikely to represent false positives due to survival bias. However, we may have a higher proportion of false negatives if inclusion of cases with a longer time to blood draw attenuated associations.
From a set of tag SNPs in 148 genes critical to innate immunity, our pooled study of adult glioma identified six genetic regions of major interest (SELP, SOD1, ALOX5 for glioma; SELP, DEFB126/127, SERPINI1, LY96 for GBM). We note the consistent association observed for SELP rs2236868 for glioma and GBM, in the NCI and NIOSH studies. This is the first report of these associations to our knowledge. Replication of these findings in large studies, such as consortial efforts of brain tumors with increased coverage of the identified genes of interest, will be essential.