Polymorphisms in the interleukin-4 receptor gene are associated with better survival in patients with glioblastoma

Abstract

Purpose: Previous literature provides some evidence that atopic diseases, IgE levels, and inflammatory gene polymorphisms may be associated with risk of glioblastoma. The purpose of this study was to investigate the effects of certain inflammatory gene single nucleotide polymorphisms (SNP) on patient survival. Malignant gliomas are the most common type of primary brain tumor in adults, however, few prognostic factors have been identified.

Experimental design: Using 694 incident adult glioma cases identified between 2001 and 2006 in Harris County, TX, we examined seven SNPs in the interleukin (IL)-4, IL-13, and IL-4 receptor (IL4R) genes. Cox proportional hazards regression was used to examine the association between the SNPs and overall and long-term survival, controlling for age at diagnosis, time between diagnosis and registration, extent of surgical resection, radiation therapy, and chemotherapy.

Results: We found that among high-grade glioma cases, IL4R rs1805016 (TT versus GT/GG) was significantly protective against mortality over time [hazard ratios (HR), 0.59; 95% confidence intervals (CI), 0.40-0.88]. The IL4R rs1805016 and rs1805015 TT genotypes were both found to be significantly associated with survival beyond 1 year among patients with high-grade glioma (HR, 0.44; 95% CI, 0.27-0.73 and HR, 0.63; 95% CI, 0.44-0.91, respectively). Furthermore, the IL4R haplotype analysis showed that SNPs in the IL4R gene may be interacting to affect long-term survival among high-grade glioma cases.

Conclusions: These findings indicate that polymorphisms in inflammation pathway genes may play an important role in glioma survival. Further research on the effects of these polymorphisms on glioma prognosis is warranted.

Figure 1. Kaplan-Meier survival curves beyond 12 months by genotype for IL4R SNPs among high-grade gliomas

(A) Patients with the TT genotype for IL4R rs1805016 SNP experienced a median survival 4 months longer than those with the GT/GG genotypes. (B) Patients with the TT genotype for IL4R rs1805015 SNP experienced a median survival of 5 months longer than those with the CT/CC genotypes. The benefit of the TT genotypes seemed to increase as the patients lived longer.

Figure 2. Conditional yearly survival estimates for IL4R SNPs and Haplotype among high-grade gliomas

Patients with the TT genotype for either SNP or with the A-T-T-A-T haplotype experienced better survival beyond one year when compared to other genotypes or haplotypes. This is consistent with and supports both the Cox regression models and the Kaplan-Meier curves for these SNPs and the haplotype. These genotypic differences were not experienced by patients with low-grade or anaplastic tumors.