Association between Prediagnostic Allergy-Related Serum Cytokines and Glioma

Abstract

Allergy is inversely related to glioma risk. To determine whether prediagnostic allergy-related serum proteins are associated with glioma, we conducted a nested case-control study of seven cytokines (IL4, IL13, IL5, IL6, IL10, IFNG, TGFB2), two soluble cytokine receptors (sIL4RA, sIL13RA2) and three allergy-related transcription factors (FOXP3, STAT3, STAT6) using serum specimens from the Janus Serum Bank Cohort in Oslo, Norway. Blood donors subsequently diagnosed with glioma (n = 487) were matched to controls (n = 487) on age and date of blood draw and sex. We first estimated individual effects of the 12 serum proteins and then interactions between IL4 and IL13 and their receptors using conditional logistic regression. We next tested equality of case-control inter-correlations among the 12 serum proteins. We found that TGFB2 is inversely related to glioblastoma (Odds Ratio (OR) = 0.87, 95% Confidence Interval (CI)) = 0.76, 0.98). In addition, ≤ 5 years before diagnosis, we observed associations between IL4 (OR = 0.82, 95% CI = 0.66, 1.01), sIL4RA (OR = 0.80, 95% CI = 0.65, 1.00), their interaction (OR = 1.06, 95% CI = 1.01, 1.12) and glioblastoma. This interaction was apparent > 20 years before diagnosis (IL4-sIL4RA OR = 1.20, 95% CI = 1.05, 1.37). Findings for glioma were similar. Case correlations were different from control correlations stratified on time before diagnosis. Five years or less before diagnosis, correlations among case serum proteins were weaker than were those among controls. Our findings suggest that IL4 and sIL4RA reduce glioma risk long before diagnosis and early gliomagenesis affects circulating immune function proteins.

A nested case-control study of 277 prediagnostic serum cytokines and glioma

“…The study population has previously been described in detail [18]. Here we briefly note its salient features.…”

“…Analytic methods are discussed in detail elsewhere [18], here we briefly summarize these methods. Cytokine array kits, consisting of a combination of two Human Cytokine Antibody Arrays (G2000, n = 174 and G4000, n = 274) from RayBiotech, Inc. (Norcross, Georgia) were used to measure 277 serum cytokines, soluble cytokine receptors and transcription factors.…”

“…In the glioma microenvironment they are eventually appropriated by the tumor and assist in immune suppression and tumor invasion [9, 14]. Because of their obvious relevance to gliomagenesis there are several studies of the relationship between cytokines and glioma after diagnosis [15–17], however, our previous study of 12 allergy and glioma related serum cytokines is the only known examination of prediagnostic serum cytokines and glioma [18]. In that study we found an interaction between interleukin 4 (IL4), a cytokine active in allergy [19] and normal brain function [20]), and its soluble receptor, interleukin 4 receptor alpha (sIL4RA).…”

“…In that study we found an interaction between interleukin 4 (IL4), a cytokine active in allergy [19] and normal brain function [20]), and its soluble receptor, interleukin 4 receptor alpha (sIL4RA). One goal of the present study was to determine whether we would identify additional associations between individual prediagnostic serum cytokines and subsequent diagnosis of glioma and, if so, whether the previously observed interaction between IL4 and sIL4RA [18] would persist in their presence. A difference between our previous and present study is that, because of small numbers of glioblastoma cases in the five years before diagnosis (n = 22), we did not analyze the data separately by this subgroup in the present study.…”

Immune factors and viral interactions in brain cancer etiology and outcomes, The 2016 Brain Tumor Epidemiology Consortium Meeting report

“…Epidemiologists have observed more gliomas among persons who do not have allergies and a history of weak responses to a neurotropic virus Varicella (i.e., lack of chickenpox and shingles) [3], which may be related to poor immune recognition of CNS-related antigens. Additional epidemiologic analyses relating to immune function include multiplex screening for cytokines in glioma cases and controls [4] and the enumeration of blood cell types using DNA methylation profiling [5]. …”