An International Case-Control Study of Interleukin-4Rα, Interleukin-13, and Cyclooxygenase-2 Polymorphisms and Glioblastoma Risk

Abstract

Previous studies found that allergies are inversely related to risk of glioma. In an earlier publication, using data from a Swedish case-control study, Schwartzbaum et al. report an inverse relation between risk of glioblastoma and four single nucleotide polymorphisms (SNP) on two genes [interleukin (IL)-4Ra, IL-13] that are associated with allergies. In addition, recent studies suggest that IL-4 and IL-13 induce cyclooxygenase-2 (COX-2) to resolve brain inflammation. To see whether previous Swedish results (110 cases, 430 controls) would be replicated, we estimated the association between glioblastoma and two IL-4Ra (rs1805015, rs1801275) and two IL-13 (rs20541, rs1800925) SNPs and their haplotypes and one COX-2 SNP (À765GC) using additional English, Danish, and Finnish data (217 cases, 1,171 controls). Among general population controls, we evaluated associations between these haplotypes, the COX-2 SNP, and self-reported allergies. Our data did not support our original observations relating individual IL-4Ra, IL-13, or COX-2 SNPs to glioblastoma risk. However, the T-G IL-4Ra haplotype was associated with glioblastoma risk (odds ratio, 2.26; 95% confidence interval, 1.13-4.52) and there was a suggestion of an inverse relation between this haplotype and hayfever prevalence among controls (odds ratio, 0.38; 95% confidence interval, 0.14-1.03). The lack of support for a link between four IL-4Ra and IL-13 SNPs and glioblastoma may reflect the absence of associations or may result from uncontrolled confounding by haplotypes related both to those that we examined and glioblastoma. Nonetheless, the association between the T-G IL-4Ra haplotype and glioblastoma risk may indicate a role of immune factors in glioblastoma development. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2448 -54) Glioblastoma, an aggressive primary malignant brain tumor, is the most common type of adult glioma and has a poor prognosis with only f3% of glioblastoma patients surviving 5 years after diagnosis (0.3% for people older than 65 years at diagnosis; ref. 1). Inherited syndromes account for only a small proportion of glioblastoma but familial aggregation of this tumor has been observed (2). The strongest known environmental risk factor for glioma is exposure to therapeutic doses of ionizing radiation (3); however, this risk factor accounts for only a small proportion of cases. In addition, evidence from one cohort and nine case-control studies (e.g., refs. 4-6) is consistent for an inverse association between self-reported asthma and allergic conditions and risk of glioma. Wiemels et al. (7) found that glioma patients have lower serum IgE levels than controls; however, the possibility that immunosuppression by the tumor itself or by its standard treatment with immunosuppressive drugs may lower IgE levels or eliminate allergies cannot be excluded.IL-4 and IL-13 are genes that share a common IL-4Ra chain on their receptors and code cytokines (immunoregulatory proteins) that share functions. TheseCancer Epidemiol Biomarkers Prev

Long-term Anti-inflammatory and Antihistamine Medication Use and Adult Glioma Risk

“…Stronger support for a protective association with asthma is suggested by one study reporting that, compared with controls, cases were less likely to carry polymorphisms in the IL4RA and IL13 genes that increase the risk for asthma and more likely to carry polymorphisms that decrease the risk for asthma (11). However, these findings were not replicated when the authors repeated their analysis in a larger pooled data set (12), and Turner et al (22) were unable to show differences in brain tumor mortality among a cohort of asthma and hay fever suffers in the United States.…”

“…Epidemiologic studies suggest a lower risk for gliomas among people reporting a history of allergies and asthma (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Schwartzbaum et al (11) reported that asthma susceptibility gene polymorphisms in IL4RA and IL13 were associated with a decreased risk for adult gliomas; however, they were unable to show significance in a larger analysis (12). Another report suggested a reduced risk for glioma with the use of nonsteroidal antiinflammatory drugs (NSAID; ref.…”

Molecular Epidemiology of Primary Brain Tumors

“…A pooled analysis of nine population-based studies failed to establish NOCs as a causal agent for glioma. 85 PBTs molecular epidemiologic studies with focus on inflammation An inverse association between IL-4RA, IL-13, and glioblastoma was observed and the relationship was not affected by allergic conditions (Table 4 [86][87][88][89][90][91][92] ). The studies also provide evidence to establish allergies as a risk factor for glioma and thus urge the identification of more candidate genes to be studied under this category.…”

ThelL-8andIL-13Gene Polymorphisms in Inflammatory Bowel Disease and Colorectal Cancer

“…Trials concerning the role of the IL-13 -1112 C/T polymorphism in cancer development were performed in an Iranian population, but neither in lung cancer nor breast cancer, there was no association observed Sameni et al, 2009). The similar trials were performed on a mixed population in patients with glioma, but there was also no connection indicated between the IL-13 -1112 C/T polymorphic variants and cancer occurrence (Schwartzbaum et al, 2007).…”