RESEARCH ARTICLE

Association of the interleukin-4Rα rs1801275 and rs1805015polymorphisms with glioma risk

Jun Guo & Lei Shi & Min Li & Jin Xu & Shushan Yan &

Chuang Zhang & Guan Sun

Received: 5 July 2013 /Accepted: 5 August 2013# International Society of Oncology and BioMarkers (ISOBM) 2013

Abstract Potential single-nucleotide polymorphisms (SNPs)of interleukin-4 receptor alpha (IL-4Rα) rs1801275 andrs1805015 have been implicated in glioma risk; however, thefindings of previous published case–control studies areconflicting and inconclusive. We performed the updated meta-analysis with the aim to provide a more precise estimate for therole of interleukin-4Rα SNPs in glioma risk. The pooled oddsratios (ORs) with 95 % confidence intervals (CIs) were used toevaluate the strength of the gene association. Overall, the pooledanalysis showed that the IL-4Rα rs1801275 polymorphism wasassociated with a decreased risk of glioma in the comparison ofG vs. A (OR=0.87, 95 % CI=0.76–0.99, POR=0.041). Sub-group analysis by ethnicity revealed that the IL-4Rα rs1801275

variant G and GG + AG exerted a decreased risk effect on thedevelopment of glioma among Asians, but not Caucasians (Gvs. A, OR=0.81, 95 % CI=0.69–0.95, POR=0.011; GG + AGvs. AA, OR=0.80, 95 % CI=0.66–0.96, POR=0.018). Howev-er, the IL-4Rα rs1805015 polymorphism did not modify the riskof glioma. Sensitivity analysis confirmed the reliability for all ofthe results. Ourmeta-analysis suggests that the polymorphism ofIL-4Rα rs1801275 but not IL-4Rα rs1805015 plays a protectiverole in the glioma pathogenesis, particularly among Asians.

Keywords Interleukin-4Rα . Glioma . Single-nucleotidepolymorphism .Meta-analysis

Introduction

Glioma is one of the most aggressive human tumors andaccounts for approximately 80 % of primary malignant braintumors with a high rate of mortality [1]. The most frequent andmost malignant histological type of glioma is glioblastoma,and higher age is the most significant predictor of poor out-come for patients with glioblastoma [2]. The only well-established environmental factor related to an elevated risk ofglioma is therapeutic X-irradiation [3]. Besides, occupationalfactors, environmental carcinogens, and dietary habits havebeen reported to play roles in the development of glioma [3].Increasing evidence has suggested that the allergic conditions,such as asthma, hay fever, and eczema, are negatively associ-ated with the risk of brain tumors, indicating a potential inter-action of allergic inflammation and brain tumorigenesis [4–6].Inflammation-related genes, such as interleukin-4 (IL-4), IL-13, and IL-4 receptor alpha (IL-4Rα), are critical in allergy,and their single-nucleotide polymorphisms (SNPs) may alterthe risk of glioma possibly by affecting the immune state [7, 8].

IL-4 and IL-13 are inflammatory cytokines sharing a com-mon IL-4Rα chain on their receptors and similar immunoreg-ulatory functions [9]. Previous studies have provided strong

Jun Guo, Lei Shi, and Min Li contributed equally to this work.

J. Guo : J. Xu :G. Sun (*)Department of Neurosurgery, Fourth Affiliated Hospital of NantongUniversity, First Hospital of Yancheng, Yancheng 224001, People’sRepublic of Chinae-mail: guansundoc@sina.com

L. ShiDepartment of Neurosurgery, The First People’s Hospital of KunshanAffiliated with Jiangsu University, Suzhou 215300, People’sRepublic of China

M. LiDepartment of Neurosurgery, Jiangning Hospital Affiliatedwith Nanjing Medical University, Nanjing 211100, People’sRepublic of China

S. YanDepartment of Surgical Oncology, The Eighty-First Hospitalof People’s Liberation Army, Nanjing 210002, People’sRepublic of China

C. Zhang (*)Department of Medical Oncology, The Eighty-First Hospitalof People’s Liberation Army, Nanjing 210002, People’sRepublic of Chinae-mail: chuangzhang2008@sina.cn

Tumor Biol.DOI 10.1007/s13277-013-1080-9

evidence for the vital effect of IL-4Rα and IL-13 genes on IgEproduction and allergy [10, 11]. Mutations in IL-4Rα can leadto abnormal immunoregulatory functions and, thus, contributeto the development of brain tumors, including glioma. Anumber of epidemiological studies have investigated the poly-morphisms of IL-4Rα rs1801275 and IL-4Rα rs1805015 inglioma risk; however, the results were conflicting and incon-clusive. The aim of this study was to provide a more preciseestimate for the role of interleukin-4Rα SNPs in glioma riskby pooling available data from published case–control studies.

Materials and methods

Search strategy

A comprehensive literature search was conducted for relevantpublications using the following keywords: “interleukin-4Rα,” “IL-4Rα,” “rs1801275,” “rs1805015,” “polymor-phism,” “single-nucleotide polymorphism,” “SNP,” “glioma,”and “brain tumor” in the PubMed and Embase databases (thelast search update was July 2013). Potentially additional stud-ies were identified by a hand search of the references ofretrieved studies. There were no language restrictions.

Inclusion criteria

The inclusion criteria were as follows: (1) case–control de-sign, (2) association between the IL-4Rα polymorphism andglioma risk, and (3) available allele and genotype frequencies.Studies not in a case–control design, without available data orwith overlapping data, were all excluded.

Data extraction

Two investigators independently extracted data, and the dis-agreements were resolved by consensus on all items. Thefollowing data were extracted: the first author’s name, publi-cation year, country of origin, ethnicity, source of controls,diagnosis of glioma, genotyping methods, matching criteria,number of cases and controls, genotype frequencies for casesand controls, sample size, and Hardy–Weinberg equilibrium(HWE) of controls.

Statistical analysis

The strength of the association between IL-4Rα rs1801275 andIL-4Rα rs1805015 polymorphisms and glioma risk was esti-mated by odds ratios (ORs) with corresponding 95 % confi-dence intervals (CIs). The genetic contrast models for IL-4Rars1801275 were as follows: G vs. A, GG vs. AA, AG vs. AA,GG+AGvs. AA, andGGvs. AA+AG. The relationship of IL-

4Ra rs1805015 polymorphism with glioma risk was assessedunder the models of C vs. T, CC vs. TT, TC vs. TT, CC + TC vs.TT, and CC vs. TT + TC. Heterogeneity analysis was evaluatedwith a chi-square-basedQ test and I2 test [12, 13]. The P valuegreater than 0.05 in combinationwith I2 less than 50% indicatesa lack of heterogeneity among studies, and the pooled OR wascalculated by a fixed effect model (the Mantel–Haenszel meth-od) [14]; otherwise, the random effect model by DerSimonianand Laird’s method was applied when heterogeneity was signif-icant [15]. Begg’s funnel plots and Egger’s linear regression testwere used to observe the potential publication bias risk amongincluded studies [16, 17]. All statistical analyses were done withthe Stata software (version 11.0; StataCorp LP, College Station,TX) by use of two-sided P values.

Results

Summary characteristics of all eligible studies

Figure 1 shows the flow chart for studies on the associationbetween the IL-4Rα polymorphism and glioma risk.According to the inclusion criteria, five publications wereeligible [8, 18–21]. The paper by Schwartzbaum et al. wasconducted among different populations, and it was dividedinto four independent studies [19]. Totally, there were eightindividual case–control studies included into the present meta-analysis [8, 18–21]. Eight independent studies with 1,678cases and 3,296 controls were related to the IL-4Rαrs1801275 polymorphism [8, 18–21]. Six individual publica-tions involving 935 cases and 2,312 controls were associated

Studies identified after searching the

PubMed and Embase databases

(n=59)

Studies retrieved after checking out the full texts(n=12)

Studies excluded after reading the abstracts:19-Irrelevant studies12-Not about the risk for glioma9-Not regarding the IL-4Rα polymorphisms5-Animal studies1-meta-analysis1-Reviews

Eligible publications with 8 independent

case-control studies

(n=5)

Studies excluded:4-Insufficient available data2-Reviews1-Case-only studies

Fig. 1 Flow chart for relevant studies

Tumor Biol.

with the mutation of IL-4Rα rs1805015 [18, 19, 21]. Amongthe eight studies, only one was in a hospital-based case–control design [20], while the others were population-basedcase–control studies [8, 18, 19, 21]. Among the eight studies,three were performed in Asians [8, 20, 21], and five were inCaucasians [18, 19]. The summary characteristics of all stud-ies were presented in Table 1. The IL-4Rα rs1801275 and IL-4Rα rs1805015 genotype distribution in the controls of allstudies did not deviate from the HWE.

The IL-4Rα rs1801275 polymorphism

As shown in Table 2 and Fig. 2, the results of the meta-analysis suggested that the IL-4Rα rs1801275 polymorphismseemed to play a protective role in the glioma developmentunder the allele comparison (G vs. A, OR=0.87, 95 % CI=0.76–0.99, POR=0.041). However, no significant associationwas observed in the other comparisons (GG vs. AA, OR=0.68, 95 % CI=0.44–1.06, POR=0.087; AG vs. AA, OR=0.82, 95 % CI=0.61–1.11, POR=0.206; GG + AG vs. AA,OR=0.94, 95 % CI=0.74–1.20, POR=0.614; GG vs. AA +AG, OR=0.69, 95 % CI=0.45–1.17, POR=0.099) (Table 2).In the subgroup analysis by ethnicity, the IL-4Rα rs1801275variant G and GG + AG was significantly associated with adecreased risk of glioma among Asians (G vs. A, OR=0.81,95 % CI=0.69–0.95, POR=0.011; GG + AG vs. AA, OR=0.80, 95 % CI=0.66–0.96, POR=0.018) (Table 2, Fig. 2). Inaddition, the IL-4Rα rs1801275 polymorphism did not corre-late with the risk of glioma in Caucasians and studies inpopulation-based case–control designs (Table 2). Neverthe-less, other genetic comparisons except the model of GG + AGvs. AAwere not investigated in the Caucasian population forunavailable data in the included studies.

The IL-4Rα rs1805015 polymorphism

The pooled ORs in overall and subgroup analyses by ethnicityall showed that the IL-4Rα rs1805015 polymorphism did notexert a significant effect on the pathogenesis of glioma (Table 2).However, we failed to estimate this association in Asians due toinsufficient data. Besides, the correlation of the IL-4Rαrs1805015 mutation with glioma risk was only assessed in thedominant model of CC + TC vs. TT (Table 2).

Publication bias

As shown in Fig. 3, Begg’s funnel plot provided evidence thatthere was no publication bias risk in the current meta-analysis.The results of Egger’s test confirmed this finding (Table 3).

Discussion

A number of previous independent case–control studies haveestimated the relationship between the polymorphisms of IL-4Rα rs1801275 and IL-4Rα rs1805015 and the glioma riskbut have yielded inconclusive results. Additionally, a singlestudy, particularly studies with inadequate sample size, may beunderpowered to determine a true gene association. Meta-analysis by pooling all available published data takes theadvantage of reducing random error. The updated meta-analysis of eight individual case–control studies included1,678 cases and 3,296 controls for the IL-4Rα rs1801275polymorphism and 935 cases and 2,312 controls for the IL-4Rα rs1805015 polymorphism. It suggested that the polymor-phism of IL-4Rα rs1801275 but not IL-4Rα rs1805015 playeda protective role in the development of glioma, especially in

Table 1 Characteristics of the studies

Study Ethnicity Country No.(cases/controls)

Matching criteria rs1801275(cases/controls)

rs1805015(cases/controls)

Source ofcontrols

GG AG AA CC TC TT

Jin et al. [8] Asian China 72/298 Race 2/6 14/105 56/187 – – – PCC

Li et al. [21] Asian China 225/250 Race and region 2/5 62/88 161/157 0/4 30/42 196/207 PCC

Ruan et al. [20] Asian China 672/696 Age, sex, region,and frequency

14/25 196/205 462/466 – – – HCC

Schwartzbaumet al. [19]

Caucasian Sweden 109/418 Age, sex, region,and frequency

– – 54/253 – – 65/298 PCC

Schwartzbaumet al. [19]

Caucasian England 106/455 Age, sex, region,and frequency

– – 54/275 – – 63/308 PCC

Schwartzbaumet al. [19]

Caucasian Denmark 66/601 Age, sex, region,and frequency

– – 40/365 – – 46/406 PCC

Schwartzbaumet al. [19]

Caucasian Finland 44/109 Age, sex, region,and frequency

– – 32/64 – – 36/75 PCC

Wiemels et al. [18] Caucasian USA 384/469 Age, race, and gender 15/22 126/144 243/303 13/16 99/113 274/341 PCC

PCC population-based case–control study, HCC hospital-based case–control study

Tumor Biol.

the Asian population. Sensitivity analysis confirmed the reli-ability of the finding.

IL-4 is a key cytokine associated with allergy [22, 23]. Itconfers immunoregulatory activity by interacting with itscognate receptors, a complex of IL-4Rα with either the com-mon γ-chain or the IL-13R chain α1 [22–24]. As criticalinflammation-related cytokines and receptors, they exert greateffects on allergic diseases by stimulating IgE synthesis anddecreasing the secretion of pro-inflammatory cytokines bymacrophages [22–24]. Hosoyama et al. showed that IL-4Rsignaling pathway could modulate the progression of tumorcells, and it could be a promising therapeutic target for cancerby inhibiting this signaling pathway [25]. Mutations in genesof IL-4, IL-13, and their receptors may break up the balance ofcytokines network and contribute to allergy and carcinogene-sis. Inverse correlation was demonstrated between theinflammation-related genes and the risk of malignant tumors,such as squamous cell cervical cancer, pancreatic cancer, andchildhood leukemia [26–28].

Many studies have provided evidence that atopic diseases arecharacterized by a lack of immune tolerance and inverselycorrelate with glioma risk [7, 29, 30]. As suggested in some

observational studies, patients with glioma were less susceptibleto allergic diseases and harbored lower atopy-associatedIgE level [31, 32]. For the polymorphisms of IL-4Rα,Schwartzbaum and colleagues firstly reported that the T-G IL-4Rα haplotypewas associatedwith glioblastoma risk, indicatinga role of IL-4Rα variant genotype in the glioblastoma patho-genesis [19]. Ruan et al. observed that the combined polymor-phisms of IL-13 rs20541 and IL-4Rα rs1801275 conferred areduced risk effect on the glioma pathogenesis, suggesting aprotective factor for glioma [20]. However, Wiemels et al. failedto demonstrate that the IL-4 polymorphism influenced the riskof glioma via their effects on the synthesis of IgE [18]. Interest-ingly, Jin et al. found that the IL-4Rα rs1801275 polymorphismwas related to an increased risk of glioblastoma in a ChineseHan population [8]. Diverse ethnicities, genetic backgrounds,source of controls, match criteria, and genotyping methods maybe responsible for the conflicting results. We hypothesized thatthe SNPs of IL-4Rα may contribute to the development ofglioma by interfering with the cell signaling transduction andimmune state. Our previous meta-analysis showed that thevariant genotypes of IL-13 rs20541 but not IL-4Rα rs1801275were significantly associated with a decreased risk of glioma

Table 2 Meta-analysis results

OR odds ratio, 95 % CI 95 %confidence interval

Comparisons Groups Test of association Test of heterogeneity

OR 95 % CI P value I2 (%) P value

IL-4Rα rs1801275

G vs. A All 0.87 0.76–0.99 0.041 43.4 0.151

Asians 0.81 0.69–0.95 0.011 32.8 0.226

PCC 0.85 0.71–1.02 0.084 61.7 0.074

GG vs. AA All 0.68 0.44–1.06 0.087 0.0 0.682

Asians 0.58 0.33–1.04 0.069 0.0 0.657

PCC 0.79 0.44–1.41 0.427 0.0 0.633

AG vs. AA All 0.82 0.61–1.11 0.206 65.0 0.035

Asians 0.72 0.48–1.08 0.112 67.7 0.045

PCC 0.74 0.45–1.19 0.215 74.8 0.019

GG + AG vs. AA All 0.94 0.74–1.20 0.614 65.3 0.005

Caucasians 1.15 0.96–1.39 0.128 48.4 0.101

Asians 0.80 0.66–0.96 0.018 60.0 0.082

PCC 0.93 0.68–1.27 0.654 69.9 0.003

GG vs. AA + AG All 0.69 0.45–1.07 0.099 0.0 0.661

Asians 0.61 0.34–1.09 0.094 0.0 0.554

PCC 0.80 0.45–1.44 0.465 0.0 0.619

IL-4Rα rs1805015

C vs. T All 0.94 0.75–1.18 0.603 68.6 0.074

CC vs. TT All 0.80 0.40–1.60 0.521 50.9 0.154

TC vs. TT All 0.98 0.75–1.28 0.906 31.8 0.226

CC + TC vs. TT All 1.02 0.76–1.37 0.883 55.3 0.048

Caucasians 1.13 0.93–1.38 0.201 48.1 0.103

CC vs. TT + TC All 0.79 0.39–1.58 0.500 47.8 0.166

Tumor Biol.

Overall (I-squared = 43.4%, p = 0.151)

Ruan Z

Li S

Jin T

Wiemels JL

ID

Study

0.87 (0.76, 0.99)

0.89 (0.73, 1.09)

0.71 (0.50, 0.99)

0.58 (0.34, 1.00)

1.02 (0.80, 1.29)

OR (95% CI)

100.00

45.12

17.12

8.61

29.15

Weight

%

.343 1 2.92

Overall (I-squared = 32.8%, p = 0.226)

ID

Jin T

Li S

Ruan Z

Study

0.81 (0.69, 0.95)

OR (95% CI)

0.58 (0.34, 1.00)

0.71 (0.50, 0.99)

0.89 (0.73, 1.09)

100.00

Weight

12.15

24.17

63.68

%

.343 1 2.92

Overall (I-squared = 60.0%, p = 0.082)

Ruan Z

Study

a

b

c

ID

Jin T

Li S

0.80 (0.66, 0.96)

0.92 (0.73, 1.16)

OR (95% CI)

0.48 (0.26, 0.88)

0.67 (0.46, 0.99)

100.00

61.65

%

Weight

13.33

25.02

.263 1 3.8

Fig. 2 Forest plots for theassociation between the IL-4Rαrs1801275 and IL-4Rαrs1805015 polymorphisms andglioma risk. a IL-4Rα rs1801275in overall analysis, G vs. A.b IL-4Rα rs1801275 in subgroupanalysis of Asians, G vs. A.c IL-4Rα rs1801275 in subgroupanalysis of Asians, GG + AGvs. AA

Tumor Biol.

[33]. However, the number of eligible studies included into thepublished meta-analysis was limited for a comprehensive anal-ysis of the susceptibility of mutant IL-4Rα to glioma.Moreover,apart from the IL-4Rα rs1801275 polymorphism, we did notassess the effect of other common SNPs, including IL-4Rαrs1805015, on the glioma pathogenesis due to insufficient avail-able data. The updated meta-analysis of eight independent case–control studies presented strong evidence that the polymorphismof IL-4Rα rs1801275 but not IL-4Rα rs1805015 played aprotective role in the development of glioma, particularly in

the Asian population. However, more studies with high qualityare warranted to further elucidate the effect of the IL-4Rαrs1801275 polymorphism on the glioma risk in Caucasians.Furthermore, the relationship of mutant IL-4Rα rs1805015 withthe development of glioma needs further elucidation in thefuture studies.

The IL-4Rα rs1801275 polymorphismwas associated witha decreased risk of glioma in combination with the mutant IL-13 rs20541, which indicated an underlying role of gene–geneinterplay in glioma pathogenesis [20]. Nevertheless, the cur-rent meta-analysis did not estimate the role of gene–geneinteractions in the risk of glioma, and in that, the eligibleindividual studies were not enough. The study by Ruan et al.also revealed that carriers with the homozygote GG of STAT6A4610G were at an increased risk of glioma compared withthe wild-type carriers among never smokers, but not amongever and current smokers. We failed to stratify the analysisaccording to the smoking status, therapeutic X-irradiation, andother relevant environmental exposures because of insuffi-cient published data to date. Thus, the effects of environmentalfactors and gene–environment interactions on the develop-ment of glioma need to be further investigated.

There were some limitations in the present meta-analysis.Firstly, we did not investigate the association of IL-4Rαrs1801275 and IL-4Rα rs1805015 polymorphisms and gliomarisk in hospital-based case–control studies, since there wasonly one study included in such a design. Besides, the rela-tionship of the IL-4Rα rs1805015 polymorphism with gliomasusceptibility was neither estimated among Asians nor in thegenetic models of C vs. T, CC vs. TT, TC vs. TT, and CC vs.TT + TC among Caucasians for a lack of original publisheddata. Therefore, further studies may still be needed to investi-gate the precise effect of IL-4Rα rs1805015 polymorphism onthe glioma risk, particularly in the Asian and Caucasian pop-ulations. Secondly, to the best of our knowledge, according tothe histology, glioma can be divided into subtypes of glioblas-toma: astrocytoma, oligodendroglioma, ependymomas, and soon. Although Ruan et al. did not identify a significant associ-ation between the mutant IL-4Rα rs1801275 and glioblasto-ma, astrocytoma, as well as other gliomas [20], subsequentstudy may further explore the potential role of IL-4Rα SNPs in

Table 3 Egger’s test resultsModels Coefficient 95 % CI SE t P value

For IL-4Rα rs1801275

G vs. A −2.886 −9.014, 3.242 1.424 −2.03 0.180

GG vs. AA −0.079 −4.892, 4.734 1.119 −0.07 0.950

AG vs. AA −4.040 −10.537, 2.457 1.510 −2.68 0.116

GG + AG vs. AA −1.108 −5.452, 3.235 1.775 −0.62 0.555

GG vs. AA + AG 0.277 −4.597, 5.150 1.133 0.24 0.830

For IL-4Rα rs1805015

CC + TC vs. TT −2.526 −7.925, 2.873 1.945 −1.30 0.264

Begg's funnel plot with pseudo 95% confidence limitsb

logo

r

s.e. of: logor0 .2 .4

-1

-.5

0

.5

1

Begg's funnel plot with pseudo 95% confidence limitsalo

gor

s.e. of: logor

0 .2 .4

-1

-.5

0

.5

1

Fig. 3 Begg’s funnel plot for publication bias. a IL-4Rα rs1801275. bIL-4Rα rs1805015

Tumor Biol.

different histological types of glioma. Thirdly, our results werebased on unadjusted estimates. A more precise evaluation forthe gene association can be acquired by performing an adjustedestimate of individual data, if the adjusted factors such as age,sex, and smoking status are available in the included case–control studies. Last but not the least, as has been argued,further studies on the effect of gene–gene and gene–environ-ment interactions on glioma risk are encouraged to compre-hensively recognize the pathogenesis of glioma.

In summary, the meta-analysis suggests that the polymor-phism of IL-4Rα rs1801275 confers individual’s variable sus-ceptibility to glioma, particularly among Asians. Nevertheless,no significant correlation of the IL-4Rα rs1805015 polymor-phismwith glioma risk was observed. In addition, the combinedeffects of gene–gene and gene–environment interactions need tobe elucidated in the future studies to draw more comprehensiveconclusions.

Conflicts of interest None.

References

1. Schwartzbaum JA, Fisher JL, Aldape KD, Wrensch M. Epidemiologyandmolecular pathology of glioma. Nat Clin Pract Neurol. 2006;2:494–503. Quiz 1 p following 16.

2. Ohgaki H, Kleihues P. Epidemiology and etiology of gliomas. ActaNeuropathol. 2005;109:93–108.

3. Ohgaki H. Epidemiology of brain tumors. Methods Mol Biol.2009;472:323–42.

4. Wigertz A, Lonn S, Schwartzbaum J, Hall P, Auvinen A, ChristensenHC, et al. Allergic conditions and brain tumor risk. Am J Epidemiol.2007;166:941–50.

5. Schoemaker MJ, SwerdlowAJ, Hepworth SJ, van TongerenM,MuirKR, McKinney PA. History of allergic disease and risk of meningi-oma. Am J Epidemiol. 2007;165:477–85.

6. Berg-Beckhoff G, Schuz J, Blettner M, Munster E, Schlaefer K,Wahrendorf J, et al. History of allergic disease and epilepsy and riskof glioma and meningioma (INTERPHONE study group, Germany).Eur J Epidemiol. 2009;24:433–40.

7. Amirian E, Liu Y, Scheurer ME, El-Zein R, Gilbert MR, Bondy ML.Genetic variants in inflammation pathway genes and asthma inglioma susceptibility. Neuro Oncol. 2010;12:444–52.

8. Jin T, Li X, Zhang J, Wang H, Geng T, Li G, et al. Genetic associationbetween selected cytokine genes and glioblastoma in the Han Chinesepopulation. BMC Cancer. 2013;13:236.

9. Llanes E, Quiralte J, Lopez E, Sastre B, Chacartegui M, del Pozo V,et al. Analysis of polymorphisms in olive pollen allergy: IL13, IL4RA,IL5 andADRB2 genes. Int ArchAllergy Immunol. 2009;148:228–38.

10. Howard TD, Koppelman GH, Xu J, Zheng SL, Postma DS, MeyersDA, et al. Gene–gene interaction in asthma: IL4RA and IL13 in aDutch population with asthma. Am J Hum Genet. 2002;70:230–6.

11. Liu X, Beaty TH, Deindl P, Huang SK, Lau S, Sommerfeld C, et al.Associations between specific serum IgE response and 6 variants withinthe genes IL4, IL13, and IL4RA in German children: the GermanMulticenter Atopy Study. J Allergy Clin Immunol. 2004;113:489–95.

12. Cochran WG. The comparison of percentages in matched samples.Biometrika. 1950;37:256–66.

13. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring incon-sistency in meta-analyses. BMJ. 2003;327:557–60.

14. Mantel N, Haenszel W. Statistical aspects of the analysis of data fromretrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.

15. DerSimonian R, Laird N.Meta-analysis in clinical trials. Control ClinTrials. 1986;7:177–88.

16. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

17. StuckAE, Rubenstein LZ,WielandD. Bias inmeta-analysis detected bya simple, graphical test. Asymmetry detected in funnel plot was prob-ably due to true heterogeneity. BMJ. 1998;316:469. Author reply 70–1.

18. Wiemels JL, Wiencke JK, Kelsey KT, Moghadassi M, Rice T,Urayama KY, et al. Allergy-related polymorphisms influence gliomastatus and serum IgE levels. Cancer Epidemiol Biomarkers Prev.2007;16:1229–35.

19. Schwartzbaum JA, AhlbomA, Lonn S,Malmer B,Wigertz A, AuvinenA, et al. An international case–control study of interleukin-4Ralpha,interleukin-13, and cyclooxygenase-2 polymorphisms and glioblastomarisk. Cancer Epidemiol Biomarkers Prev. 2007;16:2448–54.

20. Ruan Z, Zhao Y, Yan L, Chen H, Fan W, Chen J, et al. Singlenucleotide polymorphisms in IL-4Ra, IL-13 and STAT6 genes occursin brain glioma. Front Biosci (Elite Ed). 2011;3:33–45.

21. Li S, Jin T, Zhang J, Lou H, Yang B, Li Y, et al. Polymorphisms ofTREH, IL4R and CCDC26 genes associated with risk of glioma.Cancer Epidemiol. 2012;36:283–7.

22. Chomarat P, Banchereau J. Interleukin-4 and interleukin-13: theirsimilarities and discrepancies. Int Rev Immunol. 1998;17:1–52.

23. Heller NM, GwinnWM, Donnelly RP, Constant SL, Keegan AD. IL-4 engagement of the type I IL-4 receptor complex enhances mouseeosinophil migration to eotaxin-1 in vitro. PLoS One. 2012;7:e39673.

24. Andrews AL, Holloway JW, Holgate ST, Davies DE. IL-4 receptoralpha is an important modulator of IL-4 and IL-13 receptor binding:implications for the development of therapeutic targets. J Immunol.2006;176:7456–61.

25. Hosoyama T, Aslam MI, Abraham J, Prajapati SI, Nishijo K,Michalek JE, et al. IL-4R drives dedifferentiation, mitogenesis, andmetastasis in rhabdomyosarcoma. Clin Cancer Res. 2011;17:2757–66.

26. Johnson LG, Schwartz SM, Malkki M, Du Q, Petersdorf EW,Galloway DA, et al. Risk of cervical cancer associated with allergiesand polymorphisms in genes in the chromosome 5 cytokine cluster.Cancer Epidemiol Biomarkers Prev. 2011;20:199–207.

27. Turner MC. Epidemiology: allergy history, IgE, and cancer. CancerImmunol Immunother. 2012;61:1493–510.

28. Olson SH, Orlow I, Simon J, Tommasi D, Roy P, Bayuga S, et al.Allergies, variants in IL-4 and IL-4R alpha genes, and risk of pan-creatic cancer. Cancer Detect Prev. 2007;31:345–51.

29. Curran CS, Bertics PJ. Eosinophils in glioblastoma biology. JNeuroinflammation. 2012;9:11.

30. Backes DM, Siddiq A, Cox DG, Calboli FC, Gaziano JM,Ma J, et al.Single-nucleotide polymorphisms of allergy-related genes and risk ofadult glioma. J Neurooncol. 2013;113:229–38.

31. Schwartzbaum J, Ding B, Johannesen TB, Osnes LT, Karavodin L,Ahlbom A, et al. Association between prediagnostic IgE levels andrisk of glioma. J Natl Cancer Inst. 2012;104:1251–9.

32. Calboli FC, Cox DG, Buring JE, Gaziano JM, Ma J, Stampfer M,et al. Prediagnostic plasma IgE levels and risk of adult glioma in fourprospective cohort studies. J Natl Cancer Inst. 2011;103:1588–95.

33. Sun G, Wang X, Shi L, Yue X, Fu L, Chen C, et al. Associationbetween polymorphisms in interleukin-4Ralpha and interleukin-13and glioma risk: a meta-analysis. Cancer Epidemiol. 2013;37:306–10.

Tumor Biol.