Association between interleukin-4 gene intron 3 VNTR polymorphism and cancer risk
© Duan et al.; licensee BioMed Central Ltd. 2014
Received: 10 August 2014
Accepted: 17 November 2014
Published: 30 November 2014
Interleukin-4(IL-4) is a critical inflammatory cytokine and has been involved in pathogenesis of cancer. To date, several studies have investigated the association between IL-4 intron 3 variable number of tandem repeats (VNTR) polymorphism and cancer risk in humans; however, the results remain controversial. We performed this meta-analysis to find a more conclusive association between this polymorphism and cancer risk.
Eight eligible case–control studies were identified through searching electronic databases, including 1583 cases and 1638 controls. Odds ratio (OR) and corresponding 95% confidence interval (CI) were used to estimate the strength of the association.
The results of overall analyses indicated that the variant RP2 allele was associated with a decreased cancer risk compared with the RP1 allele (RP2/RP2 vs. RP1/RP1, OR = 0.64, 95% CI = 0.44-0.94; RP2/RP2 vs. RP1/RP1 + RP1/RP2, OR = 0.75, 95% CI = 0.60-0.92; RP2 vs. RP1, OR = 0.72, 95% CI = 0.56-0.92). In subgroup analyses stratified by ethnicity, there was evidence in the Asian population for an association between this polymorphism and cancer risk (RP2/RP2 vs. RP1/RP1 + RP1/RP2, OR = 0.79, 95% CI = 0.63-0.99; RP2 vs. RP1, OR = 0.77, 95% CI = 0.61-0.97).
IL-4 intron 3 VNTR polymorphism could influence the risk of human cancer. Due to the limitations of this meta-analysis, further well-designed and functional researches should be performed to validate our results.
KeywordsCancer Interleukin-4 Polymorphism Meta-analysis
Cancer is currently a major health burden in the world which results from complicated interactions between genetic and environmental factors ,. Epidemiological studies have revealed that chronic inflammation could pose a risk factor for several cancers . Moreover, inflammation has been linked to the pathogenesis of tumors in up to 15% of human cancers . Cytokines are important inflammatory mediators and there is evidence that human predisposition to cancer could be influenced by polymorphisms located in genes encoding cytokines and their receptors .
Interleukin-4(IL-4), produced by activated Th2 type CD4+ T cells, represents a key differentiation cytokine that induces development of Th2 subset of lymphocytes, which is responsible for surveillance and clearance of tumor cells by activation of granulocytes and eosinophils, as well as inhibition of angiogenesis ,. Moreover, Th2 subset is involved in antagonizing IFN-γ function, B cell switching to IgE production, inhibiting macrophage activation and some studies have revealed its anti-tumor activity on several cancers such as colon, breast and renal carcinoma ,. However, IL-4 plays a bilateral role in the control of tumor growth. It has been reported that IL-4 could promote the initiation, progression and spread of head and neck squamous carcinoma –. Liang et al.  have found that there was a significantly higher level of IL-4 mRNA in patients with gastric cancer in stage III and IV than that in stage I and II. In addition, IL-4 also disturbs anti-tumor immunity by down-regulating the expression of Th1 cytokines , and impairing the CD8+ T cell immune response in the tumor microenvironment ,.
The gene encoding IL-4 is located on chromosome 5q31.1 . A rapidly growing number of epidemiologic studies have been conducted to investigate the effect of several IL-4 polymorphisms on human cancer risk. One important polymorphism is located in the intron 3 of IL-4 gene and is composed of a 70-bp sequence of variable number of tandem repeats (VNTR) ,. It has been proved that the IL-4 intron 3 polymorphism might influence the production of IL-4, with the RP1 (two 70-bp repeats) allele enhancing IL-4 expression compared with RP2 (three 70-bp repeats) allele ,.
To date, several case–control studies have been carried out to explore the linkage between IL-4 intron 3 VNTR polymorphism and the risk of several human cancers. However, results from different articles remain controversial. We performed this meta-analysis based on the published studies to make a more conclusive evaluation of the association between this polymorphism and cancer risk.
Materials and methods
Relevant articles indexed in PubMed and Cochrane Library (from inception to July 30, 2014) were independently searched by two authors, using the key words as follows: (“interleukin-4” or “interleukin 4” or “IL-4” or “IL 4”) and (“tumor” or “cancer” or “carcinoma” or “neoplasm” or “malignancy”) and (“polymorphism” or “polymorphisms” or “SNP” or “variant” or “variation”). The retrieved results were filtered to English language papers. An additional manual search was performed among the references of relevant articles and related articles in PubMed.
All the retrieved articles were reviewed by two authors independently to select studies for inclusion. As for studies with overlapping data reported by the same investigators, the articles with the most complete data were eligible. Studies included in this meta-analysis should meet the following predetermined criteria: 1) case–control design, 2) evaluation of the IL-4 intron 3 VNTR polymorphism and cancer risk, 3) effective estimation of odd ratio (OR) with 95% confidence interval (CI), or enough data to allow calculation of these two statistics. The major criteria for exclusion were: 1) not relevant to IL-4 polymorphism and cancer risk, 2) not with a case–control design (eg, animal studies, reviews, case reports, letters, and editorials), 3) study on inherited cancers, 4) duplicate data.
Two authors checked each included article independently to extract the necessary data. The following information were collected: first author’s last name, publication year, ethnicity of the study population, country where the study conduct, sample size, source of the control groups (hospital- or population-based), the distribution of variant genotypes of both cases and controls.
Pooled analysis was performed to estimate the strength of the association between IL-4 polymorphism and cancer risk using the odds ratio (OR) with 95% confidence interval (CI). The pooled ORs were calculated by a co-dominant model (RP2/RP2 vs. RP1/RP1, RP1/RP2 vs. RP1/RP1), a dominant model (RP2/RP2 + RP1/RP2 vs. RP1/RP1), a recessive model (RP2/RP2 vs. RP1/RP1 + RP1/RP2), and an allelic model (RP2 vs. RP1). The values of the pooled ORs were tested by Z-test . Hardy-Weinberg equilibrium (HWE) was estimated using goodness-of-fit test based on the chi-square test in the control groups of each study .
Heterogeneity among the included studies was evaluated using chi-square based on Q-test and I2 statistic . Pooled ORs were calculated using a fixed (Mantel-Haenszel method ) or random (DerSimonian-Laird method ) effective model according to the absence (I2 < 50%) or presence (I2 > 50%) of heterogeneity. Sensitivity analyses were conducted by removing one study each time to assess the stability of the results. The potential publication bias of the included studies was evaluated by Begg’s funnel plots graphically and Egger’s linear regression test .
All the tests were two sides and it is deemed to be statistically significant when P < 0.05. All the statistical analyses were carried out with Stata/SE software version 12.0 (StataCorp LP, College Station, TX, USA).
Literature search and characteristics of eligible studies
Characteristics of eligible studies in the meta-analysis
Source of controls
Pooled analysis of association between IL-4 intron 3 VNTR polymorphism and cancer risk
Test of association
Test of heterogeneity
Egger's test (P-value)
RP1/RP2 vs RP1/RP1
RP2/RP2 vs RP1/RP1
RP2/RP2+RP1/RP2 vs RP1/RP1
RP2/RP2 vs RP1/RP1+RP1/RP2
RP2 vs RP1
In addition, we omitted 1 study in which the control group was not in agreement with HWE  and repeated the meta-analysis. The result was consist with the overall analyses (RP1/RP2 vs. RP1/RP1, OR = 0.74, 95% CI = 0.49-1.13; RP2/RP2 vs. RP1/RP1, OR = 0.62, 95% CI = 0.41-0.95; RP2/RP2 + RP1/RP2 vs. RP1/RP1, OR = 0.71, 95% CI = 0.46-1.09; RP2/RP2 vs. RP1/RP1 + RP1/RP2, OR = 0.78, 95% CI = 0.61-0.98; RP2 vs. RP1, OR = 0.71, 95% CI = 0.53-0.94).
Test for heterogeneity and sensitivity analysis
Cancer is a heterogeneous disease resulting from genetics, environmental factors, and their interactions, the clinical outcome of which is difficult to predict –. Inflammation has been associated with variant malignancies. Elevated levels of inflammatory cytokines have been linked to inflammatory exacerbation. As a critical anti-inflammatory cytokine, IL-4 has implicated in the pathogenesis of various cancers. Elevated plasma levels of IL-4 were correlated with risk of acute myeloid leukemia, melanoma, head and neck squamous cell carcinoma, non-small-cell lung cancer, prostate, colon, breast, renal cell cancer –, and were associated with poor prognosis in non-Hodgkin lymphoma . More specifically, several polymorphisms of the gene encoding IL-4 have been proved to be risk factors for cancer ,–. Besides the most common polymorphisms, −590C > T(rs2243250) and -33 T > C(rs2070874), the intron 3 VNTR polymorphism also plays an important role in alteration of IL-4 production.
To our knowledge, Li et al. performed a meta-analysis about the association of IL-4 intron 3 VNTR polymorphism and cancer risk . Their results showed that there was no association between this polymorphism and cancer risk. However, some concerns were related to this meta-analysis. First, the sample size was relatively small, involving 791 cases and 772 controls from 5 case–control studies. Second, there was significant heterogeneity and the origin of heterogeneity was not well explored. In addition, several important studies about the association of IL-4 intron 3 VNTR polymorphism and cancer risk have been published recently.
The present meta-analysis, including 1583 cases and 1638 controls from 8 case–control studies, comprehensively assessed the association between IL-4 intron 3 VNTR polymorphism and risk of human cancers. We found an association between IL-4 intron 3 VNTR polymorphism and cancer risk. Our results indicated the RP1 allele might be a risk factor for malignancies. The results were robust because the pooled ORs did not alter in sensitivity analyses. Stratified analyses suggested that the association was mainly in Asian populations and in bladder cancer. Since there was significant heterogeneity in several genetic models, two studies were founded out by sensitivity analyses. We re-checked these 2 studies and found that 1 study  was the only population-based design in the 8 included studies and the other one  was the only one that conducted on a Caucasian population. In addition, we pooled the data from studies on diverse cancer types, which might contribute to some extent of the heterogeneity. Different cancer types might give rise to different host responses, and the interactions between different environmental factors and host might also influence the susceptibility to different cancer types. Because of the limited study number, we could not perform a meta-regression analysis to estimate the extent of heterogeneity from different cancer types.
Some limitations of our meta-analysis should be pointed out. First, the pooled outcomes were calculated based on unadjusted estimates, which limited a more precise evaluation on adjusted estimates by several important factors like age, sex, lifestyle and etc. Only one study reported that IL-4 intron 3 VNTR polymorphism was associated with oral and pharyngeal carcinoma risk, which interacted with alcohol drinking . Thus, lacking of these original information limited supplementary assessment of the potential interactions because gene-gene, gene-environment interactions and other polymorphisms of the same gene might influence cancer predisposition. Second, most of the studies included in the present meta-analysis only focused on the relationship between IL-4 intron 3 VNTR polymorphism and cancer risk, which made it hard to assess the effects of IL-4 haplotypes composed of different IL-4 polymorphisms on carcinogenesis. There was evidence that IL-4 -590C > T(rs2243250), −33 T > C(rs2070874) polymorphisms were associated with cancer risk ,,. Thus, the status of other IL-4 polymorphisms might cover up the impact of intron 3 VNTR polymorphism on carcinogenesis. Third, limited study number restricted us to perform additional subgroup analyses. Forth, although there was no publication bias statistically, the potential publication bias might exist because some studies with negative results were not published. Moreover, there was only one study conducted on the Caucasian population and no study on the African population in this meta-analysis.
Despite these limitations, advantages in our meta-analysis should be also acknowledged. First, the statistical power was definitely increased by pooling a substantial number of cases and controls. Second, all the eligible studies met the inclusion and exclusion criteria strictly and completely. Third, no publication bias was detected through Begg’s funnel plots and Egger’s test, which indicated that the pooled results should be unbiased.
In conclusion, the results of this meta-analysis were statistically credible. The relationship between IL-4 intron 3 VNTR polymorphism and cancer risk was assessed and this polymorphism was associated with cancer risk, mainly in Asians. To draw a more precise conclusion, further studies should be carried out with more detailed individual information, concerning the effects of other polymorphisms and haplotypes, enrolling larger sample size of cases and well-matched controls, especially in Caucasians and Africans, to validate the role of IL-4 polymorphism in carcinogenesis.
This work was granted by National Natural Science Foundation of China (Grant No.91229104).
- Hoeijmakers JH: Genome maintenance mechanisms for preventing cancer. Nature. 2001, 411 (6835): 366-374. 10.1038/35077232.View ArticlePubMedGoogle Scholar
- Bredberg A: Cancer: more of polygenic disease and less of multiple mutations? A quantitative viewpoint. Cancer. 2011, 117 (3): 440-445. 10.1002/cncr.25440.View ArticlePubMedGoogle Scholar
- Wang S, Liu Z, Wang L, Zhang X: NF-kappaB signaling pathway, inflammation and colorectal cancer. Cell Mol Immunol. 2009, 6 (5): 327-334. 10.1038/cmi.2009.43.View ArticlePubMed CentralPubMedGoogle Scholar
- Kuper H, Adami HO, Trichopoulos D: Infections as a major preventable cause of human cancer. J Intern Med. 2000, 248 (3): 171-183. 10.1046/j.1365-2796.2000.00742.x.View ArticlePubMedGoogle Scholar
- Bidwell J, Keen L, Gallagher G, Kimberly R, Huizinga T, McDermott MF, Oksenberg J, McNicholl J, Pociot F, Hardt C, D’Alfonso S: Cytokine gene polymorphism in human disease: on-line databases. Genes Immun. 1999, 1 (1): 3-19. 10.1038/sj.gene.6363645.View ArticlePubMedGoogle Scholar
- Olver S, Apte S, Baz A, Kienzle N: The duplicitous effects of interleukin 4 on tumour immunity: how can the same cytokine improve or impair control of tumour growth?. Tissue Antigens. 2007, 69 (4): 293-298. 10.1111/j.1399-0039.2007.00831.x.View ArticlePubMedGoogle Scholar
- Swain SL, Weinberg AD, English M, Huston G: IL-4 directs the development of Th2-like helper effectors. J Immunol. 1990, 145 (11): 3796-3806.PubMedGoogle Scholar
- Toi M, Bicknell R, Harris AL: Inhibition of colon and breast carcinoma cell growth by interleukin-4. Cancer Res. 1992, 52 (2): 275-279.PubMedGoogle Scholar
- Yu SJ, Kim HS, Cho SW, Sohn J: IL-4 inhibits proliferation of renal carcinoma cells by increasing the expression of p21WAF1 and IRF-1. Exp Mol Med. 2004, 36 (4): 372-379. 10.1038/emm.2004.49.View ArticlePubMedGoogle Scholar
- Myers JN, Yasumura S, Suminami Y, Hirabayashi H, Lin W, Johnson JT, Lotze MT, Whiteside TL: Growth stimulation of human head and neck squamous cell carcinoma cell lines by interleukin 4. Clin Cancer Res. 1996, 2 (1): 127-135.PubMedGoogle Scholar
- Manchanda P, Sharma SC, Das SN: Differential regulation of IL-2 and IL-4 in patients with tobacco-related oral squamous cell carcinoma. Oral Dis. 2006, 12 (5): 455-462. 10.1111/j.1601-0825.2005.01220.x.View ArticlePubMedGoogle Scholar
- Agarwal A, Rani M, Saha GK, Valarmathi TM, Bahadur S, Mohanti BK, Das SN: Disregulated expression of the Th2 cytokine gene in patients with intraoral squamous cell carcinoma. Immunol Investig. 2003, 32 (1–2): 17-30. 10.1081/IMM-120019205.View ArticleGoogle Scholar
- Yamamoto T, Yoneda K, Ueta E, Hirota J, Osaki T: Serum cytokine levels in patients with oral mucous membrane disorders. J Oral Pathol Med. 1991, 20 (6): 275-279. 10.1111/j.1600-0714.1991.tb00927.x.View ArticlePubMedGoogle Scholar
- Liang J, Li Y, Liu X, Xu X, Zhao Y: Relationship between cytokine levels and clinical classification of gastric cancer. Asian Pac J Cancer Prev. 2011, 12 (7): 1803-1806.PubMedGoogle Scholar
- Goto T, Nishizono A, Fujioka T, Ikewaki J, Mifune K, Nasu M: Local secretory immunoglobulin A and postimmunization gastritis correlate with protection against Helicobacter pylori infection after oral vaccination of mice. Infect Immun. 1999, 67 (5): 2531-2539.PubMed CentralPubMedGoogle Scholar
- Serefoglou Z, Yapijakis C, Nkenke E, Vairaktaris E: Genetic association of cytokine DNA polymorphisms with head and neck cancer. Oral Oncol. 2008, 44 (12): 1093-1099. 10.1016/j.oraloncology.2008.02.012.View ArticlePubMedGoogle Scholar
- Rosenwasser LJ, Klemm DJ, Dresback JK, Inamura H, Mascali JJ, Klinnert M, Borish L: Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Allergy. 1995, 25 (Suppl 2): 74-78. 10.1111/j.1365-2222.1995.tb00428.x. discussion 95–76View ArticlePubMedGoogle Scholar
- Mout R, Willemze R, Landegent JE: Repeat polymorphisms in the interleukin-4 gene (IL4). Nucleic Acids Res. 1991, 19 (13): 3763-10.1093/nar/19.13.3763.View ArticlePubMed CentralPubMedGoogle Scholar
- Nakashima H, Miyake K, Inoue Y, Shimizu S, Akahoshi M, Tanaka Y, Otsuka T, Harada M: Association between IL-4 genotype and IL-4 production in the Japanese population. Genes Immun. 2002, 3 (2): 107-109. 10.1038/sj.gene.6363830.View ArticlePubMedGoogle Scholar
- Breslow NE, Day NE: Statistical methods in cancer research. Volume II--The design and analysis of cohort studies.IARC Sci Publ 1987, (82):1–406.,Google Scholar
- Haber M: Exact significance levels of goodness-of-fit tests for the Hardy-Weinberg equilibrium. Hum Hered. 1981, 31 (3): 161-166. 10.1159/000153199.View ArticlePubMedGoogle Scholar
- Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses. BMJ. 2003, 327 (7414): 557-560. 10.1136/bmj.327.7414.557.View ArticlePubMed CentralPubMedGoogle Scholar
- Mantel N, Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959, 22 (4): 719-748.PubMedGoogle Scholar
- DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials. 1986, 7 (3): 177-188. 10.1016/0197-2456(86)90046-2.View ArticlePubMedGoogle Scholar
- Sterne JA, Gavaghan D, Egger M: Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000, 53 (11): 1119-1129. 10.1016/S0895-4356(00)00242-0.View ArticlePubMedGoogle Scholar
- Tsai FJ, Chang CH, Chen CC, Hsia TC, Chen HY, Chen WC: Interleukin-4 gene intron-3 polymorphism is associated with transitional cell carcinoma of the urinary bladder. BJU Int. 2005, 95 (3): 432-435. 10.1111/j.1464-410X.2005.05315.x.View ArticlePubMedGoogle Scholar
- Tsai MH, Chen WC, Tsai CH, Hang LW, Tsai FJ: Interleukin-4 gene, but not the interleukin-1 beta gene polymorphism, is associated with oral cancer. J Clin Lab Anal. 2005, 19 (3): 93-98. 10.1002/jcla.20060.View ArticlePubMedGoogle Scholar
- Lai KC, Chen WC, Jeng LB, Li SY, Chou MC, Tsai FJ: Association of genetic polymorphisms of MK, IL-4, p16, p21, p53 genes and human gastric cancer in Taiwan. Eur J Surg Oncol. 2005, 31 (10): 1135-1140. 10.1016/j.ejso.2005.07.005.View ArticlePubMedGoogle Scholar
- Kesarwani P, Ahirwar DK, Mandhani A, Mittal RD: Association between −174 G/C promoter polymorphism of the interleukin-6 gene and progression of prostate cancer in North Indian population. DNA Cell Biol. 2008, 27 (9): 505-510. 10.1089/dna.2008.0742.View ArticlePubMedGoogle Scholar
- Konwar R, Chaudhary P, Kumar S, Mishra D, Chattopadhyay N, Bid HK: Breast cancer risk associated with polymorphisms of IL-1RN and IL-4 gene in Indian women. Oncol Res. 2009, 17 (8): 367-372. 10.3727/096504009788428442.View ArticlePubMedGoogle Scholar
- Shekari M, Kordi-Tamandani DM, MalekZadeh K, Sobti RC, Karimi S, Suri V: Effect of anti-inflammatory (IL-4, IL-10) cytokine genes in relation to risk of cervical carcinoma. Am J Clin Oncol. 2012, 35 (6): 514-519. 10.1097/COC.0b013e31822d9c12.View ArticlePubMedGoogle Scholar
- Yang CM, Chen HC, Hou YY, Lee MC, Liou HH, Huang SJ, Yen LM, Eng DM, Hsieh YD, Ger LP: A high IL-4 production diplotype is associated with an increased risk but better prognosis of oral and pharyngeal carcinomas. Arch Oral Biol. 2014, 59 (1): 35-46. 10.1016/j.archoralbio.2013.09.010.View ArticlePubMedGoogle Scholar
- Bozdogan ST, Erol B, Dursun A, Bozdogan G, Donmez I, Mungan NA, Seydaoglu G: The IL-1RN and IL-4 gene polymorphisms are potential genetic markers of susceptibility to bladder cancer: a case–control study.World J Urol 2014, [Epub ahead of print].,Google Scholar
- Zhang H, Xu Y, Zhang Z, Liu R, Ma B: Association between COX-2 rs2745557 polymorphism and prostate cancer risk: a systematic review and meta-analysis. BMC Immunol. 2012, 13: 14-10.1186/1471-2172-13-14.View ArticlePubMed CentralPubMedGoogle Scholar
- Zhang H, Qi C, Li L, Luo F, Xu Y: Clinical significance of NUCB2 mRNA expression in prostate cancer. J Exp Clin Cancer Res. 2013, 32 (1): 56-10.1186/1756-9966-32-56.View ArticlePubMed CentralPubMedGoogle Scholar
- Abaza MS, Bahman AM, Al-Attiyah RJ, Kollamparambil AM: Synergistic induction of apoptosis and chemosensitization of human colorectal cancer cells by histone deacetylase inhibitor, scriptaid, and proteasome inhibitors: potential mechanisms of action. Tumour Biol. 2012, 33 (6): 1951-1972. 10.1007/s13277-012-0456-6.View ArticlePubMedGoogle Scholar
- Sanchez-Correa B, Bergua JM, Campos C, Gayoso I, Arcos MJ, Banas H, Morgado S, Casado JG, Solana R, Tarazona R: Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels. Cytokine. 2013, 61 (3): 885-891. 10.1016/j.cyto.2012.12.023.View ArticlePubMedGoogle Scholar
- Porter GA, Abdalla J, Lu M, Smith S, Montgomery D, Grimm E, Ross MI, Mansfield PF, Gershenwald JE, Lee JE: Significance of plasma cytokine levels in melanoma patients with histologically negative sentinel lymph nodes. Ann Surg Oncol. 2001, 8 (2): 116-122. 10.1007/s10434-001-0116-3.View ArticlePubMedGoogle Scholar
- Lathers DM, Young MR: Increased aberrance of cytokine expression in plasma of patients with more advanced squamous cell carcinoma of the head and neck. Cytokine. 2004, 25 (5): 220-228. 10.1016/j.cyto.2003.11.005.View ArticlePubMedGoogle Scholar
- Shurin MR, Lu L, Kalinski P, Stewart-Akers AM, Lotze MT: Th1/Th2 balance in cancer, transplantation and pregnancy. Springer Semin Immunopathol. 1999, 21 (3): 339-359. 10.1007/BF00812261.View ArticlePubMedGoogle Scholar
- Mellgren K, Hedegaard CJ, Schmiegelow K, Muller K: Plasma cytokine profiles at diagnosis in pediatric patients with non-hodgkin lymphoma. J Pediatr Hematol Oncol. 2012, 34 (4): 271-275. 10.1097/MPH.0b013e3182431e02.View ArticlePubMedGoogle Scholar
- Pan XF, Wen Y, Loh M, Wen YY, Yang SJ, Zhao ZM, Tian Z, Huang H, Lan H, Chen F, Soong R, Yang CX: Interleukin-4 and −8 gene polymorphisms and risk of gastric cancer in a population in Southwestern China. Asian Pac J Cancer Prev. 2014, 15 (7): 2951-2957. 10.7314/APJCP.2014.15.7.2951.View ArticlePubMedGoogle Scholar
- Jin T, Li X, Zhang J, Wang H, Geng T, Li G, Gao G, Chen C: Genetic association between selected cytokine genes and glioblastoma in the Han Chinese population. BMC Cancer. 2013, 13: 236-10.1186/1471-2407-13-236.View ArticlePubMed CentralPubMedGoogle Scholar
- Monroy CM, Cortes AC, Lopez MS, D’Amelio AM, Etzel CJ, Younes A, Strom SS, El-Zein RA: Hodgkin disease risk: role of genetic polymorphisms and gene-gene interactions in inflammation pathway genes. Mol Carcinog. 2011, 50 (1): 36-46. 10.1002/mc.20688.View ArticlePubMedGoogle Scholar
- Olson SH, Orlow I, Simon J, Tommasi D, Roy P, Bayuga S, Ludwig E, Zauber AG, Kurtz RC: Allergies, variants in IL-4 and IL-4R alpha genes, and risk of pancreatic cancer. Cancer Detect Prev. 2007, 31 (5): 345-351. 10.1016/j.cdp.2007.10.002.View ArticlePubMedGoogle Scholar
- Zhenzhen L, Xianghua L, Qingwei W, Zhan G, Ning S: Three common polymorphisms in the IL-4 gene and cancer risk: a meta-analysis involving 5,392 cases and 6,930 controls. Tumour Biol. 2013, 34 (4): 2215-2224. 10.1007/s13277-013-0761-8.View ArticlePubMedGoogle Scholar
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