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Association between the interleukin-4, interleukin-13 polymorphisms and asthma: a meta-analysis

Abstract

A numbers studies had been reported that the polymorphisms in the Interleukin 4 (IL-4) and Interleukin 13 (IL-13) genes were associated with susceptibility to asthma. However, the results were inconsistent and inconclusive. We carried out a meta-analysis of case–control genetic association studies to assess whether the combined data showed this association by using a genetic model-free approach. Thirty studies (total 12,781 asthma and 11,500 controls) for the IL-4 C-33T and C-589T, IL-13 C-1112T and G+2044A with asthma were included in the meta-analysis. The results indicated that there were an association between the IL-4 C-33T (P = 0.006) and C-589T (P = 0.04), IL-13 C-1112T (P = 0.002) and G+2044A (P = 0.04) and susceptibility to asthma. And the definition of asthma subgroup meta-analysis demonstrates that the IL-4 C-33T is not associated with nonatopic or atopic, and IL-4 C-589T and IL-13 C-1112T polymorphisms are not associated with atopic. In the ethnicity subgroup meta-analysis, the IL-4 −589T (P = 0.003) and the IL-13 −1112T (P < 0.00001) alleles are associated with asthma among Caucasian, but not on the IL-13 +2044A allele. In conclusion, IL-4 C-33T and C-589T, IL-13 C-1112T and G+2044A could be proposed as asthma susceptible SNPs. Further investigation in larger studies and meta-analysis is required.

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References

  1. Adjers K, Karjalainen J, Pessi T, Eklund C, Hurme M (2005) Epistatic effect of TLR4 and IL4 genes on the risk of asthma in females. Int Arch Allergy Immunol 138:251–256

    PubMed  Article  CAS  Google Scholar 

  2. Amirzargar AA, Movahedi M, Rezaei N, Moradi B, Dorkhosh S, Mahloji M, Mahdaviani SA (2009) Polymorphisms in IL4 and iLARA confer susceptibility to asthma. J Investig Allergol Clin Immunol 19:433–438

    PubMed  CAS  Google Scholar 

  3. Basehore MJ, Howard TD, Lange LA, Moore WC, Hawkins GA, Marshik PL, Harkins MS, Meyers DA, Bleecker ER (2004) A comprehensive evaluation of IL4 variants in ethnically diverse populations: association of total serum IgE levels and asthma in white subjects. J Allergy Clin Immunol 114:80–87

    PubMed  Article  CAS  Google Scholar 

  4. Battle NC, Choudhry S, Tsai HJ, Eng C, Kumar G, Beckman KB, Naqvi M, Meade K, Watson HG, Lenoir M, Burchard EG (2007) Ethnicity-specific gene–gene interaction between IL-13 and IL-4Ralpha among African Americans with asthma. Am J Respir Crit Care Med 175:881–887

    PubMed  Article  CAS  Google Scholar 

  5. Baye TM, Butsch Kovacic M, Biagini Myers JM, Martin LJ, Lindsey M, Patterson TL, He H, Ericksen MB, Gupta J, Tsoras AM, Lindsley A, Rothenberg ME, Wills-Karp M, Eissa NT, Borish L, Khurana Hershey GK (2011) Differences in candidate gene association between European ancestry and African American asthmatic children. Plos One 6:e16522

    PubMed  Article  CAS  Google Scholar 

  6. Beghe B, Barton S, Rorke S, Peng Q, Sayers I, Gaunt T, Keith TP, Clough JB, Holgate ST, Holloway JW (2003) Polymorphisms in the interleukin-4 and interleukin-4 receptor alpha chain genes confer susceptibility to asthma and atopy in a Caucasian population. Clin Exp Allergy 33:1111–1117

    PubMed  Article  CAS  Google Scholar 

  7. Berce V, Potocnik U (2010) Association of Q551R polymorphism in the interleukin 4 receptor gene with nonatopic asthma in Slovenian children. Wien Klin Wochenschr 122(Suppl 2):11–18

    PubMed  Article  CAS  Google Scholar 

  8. Bottema RW, Nolte IM, Howard TD, Koppelman GH, Dubois AE, de Meer G, Kerkhof M, Bleecker ER, Meyers DA, Postma DS (2010) Interleukin 13 and interleukin 4 receptor-alpha polymorphisms in rhinitis and asthma. Int Arch Allergy Immunol 153:259–267

    PubMed  Article  CAS  Google Scholar 

  9. Chan IH, Tang NL, Leung TF, Huang W, Lam YY, Li CY, Wong CK, Wong GW, Lam CW (2008) Study of gene–gene interactions for endophenotypic quantitative traits in Chinese asthmatic children. Allergy 63:1031–1039

    PubMed  Article  CAS  Google Scholar 

  10. Chiang CH, Tang YC, Lin MW, Chung MY (2007) Association between the IL-4 promoter polymorphisms and asthma or severity of hyperresponsiveness in Taiwanese. Respirology 12:42–48

    PubMed  Article  Google Scholar 

  11. Cui T, Wu J, Pan S, Xie J (2003) Polymorphisms in the IL-4 and IL-4R [alpha] genes and allergic asthma. Clin Chem Lab Med 41:888–892

    PubMed  Article  CAS  Google Scholar 

  12. Cui T, Wang L, Wu J, Hu L, Xie J (2003) Polymorphisms of IL-4, IL-4R alpha, and AICDA genes in adult allergic asthma. J Huazhong Univ Sci Technolog Med Sci 23:134–137

    PubMed  Article  CAS  Google Scholar 

  13. Daley D, Lemire M, Akhabir L, Chan-Yeung M, He JQ, McDonald T, Sandford A, Stefanowicz D, Tripp B, Zamar D, Bosse Y, Ferretti V, Montpetit A, Tessier MC, Becker A, Kozyrskyj AL, Beilby J, McCaskie PA, Musk B, Warrington N, James A, Laprise C, Palmer LJ, Pare PD, Hudson TJ (2009) Analyses of associations with asthma in four asthma population samples from Canada and Australia. Hum Genet 125:445–459

    PubMed  Article  Google Scholar 

  14. de Guia RM, Ramos JD (2010) The −590C/TIL4 single-nucleotide polymorphism as a genetic factor of atopic allergy. Int J Mol Epidemiol Genet 1:67–73

    PubMed  Google Scholar 

  15. Donfack J, Schneider DH, Tan Z, Kurz T, Dubchak I, Frazer KA, Ober C (2005) Variation in conserved non-coding sequences on chromosome 5q and susceptibility to asthma and atopy. Respir Res 6:145

    PubMed  Article  Google Scholar 

  16. Freidin MB, Kobyakova OS, Ogorodova LM, Puzyrev VP (2003) Association of polymorphisms in the human IL4 and IL5 genes with atopic bronchial asthma and severity of the disease. Comp Funct Genomics 4:346–350

    PubMed  Article  CAS  Google Scholar 

  17. Gervaziev YV, Kaznacheev VA, Gervazieva VB (2006) Allelic polymorphisms in the interleukin-4 promoter regions and their association with bronchial asthma among the Russian population. Int Arch Allergy Immunol 141:257–264

    PubMed  Article  CAS  Google Scholar 

  18. Heinzmann A, Mao XQ, Akaiwa M, Kreomer RT, Gao PS, Ohshima K, Umeshita R, Abe Y, Braun S, Yamashita T, Roberts MH, Sugimoto R, Arima K, Arinobu Y, Yu B, Kruse S, Enomoto T, Dake Y, Kawai M, Shimazu S, Sasaki S, Adra CN, Kitaichi M, Inoue H, Yamauchi K, Tomichi N, Kurimoto F, Hamasaki N, Hopkin JM, Izuhara K, Shirakawa T, Deichmann KA (2000) Genetic variants of IL-13 signalling and human asthma and atopy. Hum Mol Genet 9:549–559

    PubMed  Article  CAS  Google Scholar 

  19. Hijazi Z, Haider MZ (2000) Interleukin-4 gene promoter polymorphism [C590T] and asthma in Kuwaiti Arabs. Int Arch Allergy Immunol 122:190–194

    PubMed  Article  CAS  Google Scholar 

  20. Hizawa N (2009) Genetic backgrounds of asthma and COPD. Allergol Int 58:315–322

    PubMed  Article  CAS  Google Scholar 

  21. Hosseini-Farahabadi S, Tavakkol-Afshari J, Rafatpanah H, Farid Hosseini R, Khaje Daluei M (2007) Association between the polymorphisms of IL-4 gene promoter (−590C>T), IL-13 coding region (R130Q) and IL-16 gene promoter (−295T>C) and allergic asthma. Iran J Allergy Asthma Immunol 6:9–14

    PubMed  CAS  Google Scholar 

  22. Howard TD, Whittaker PA, Zaiman AL, Koppelman GH, Xu J, Hanley MT, Meyers DA, Postma DS, Bleecker ER (2001) Identification and association of polymorphisms in the interleukin-13 gene with asthma and atopy in a Dutch population. Am J Respir Cell Mol Biol 25:377–384

    PubMed  CAS  Google Scholar 

  23. Huedo-Medina TB, Sanchez-Meca J, Marin-Martinez F, Botella J (2006) Assessing heterogeneity in meta-analysis: Q statistic or I2 index? Psychol Methods 11:193–206

    PubMed  Article  Google Scholar 

  24. Isidoro-Garcia M, Davila I, Laffond E, Moreno E, Lorente F, Gonzalez-Sarmiento R (2005) Interleukin-4 (IL4) and Interleukin-4 receptor (IL4RA) polymorphisms in asthma: a case control study. Clin Mol Allergy 3:15

    PubMed  Article  Google Scholar 

  25. Kabesch M, Tzotcheva I, Carr D, Hofler C, Weiland SK, Fritzsch C, von Mutius E, Martinez FD (2003) A complete screening of the IL4 gene: novel polymorphisms and their association with asthma and IgE in childhood. J Allergy Clin Immunol 112:893–898

    PubMed  Article  CAS  Google Scholar 

  26. Kabesch M, Schedel M, Carr D, Woitsch B, Fritzsch C, Weiland SK, von Mutius E (2006) IL-4/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma. J Allergy Clin Immunol 117:269–274

    PubMed  Article  CAS  Google Scholar 

  27. Kaishu Z, Jirong L, Shanyu L, Zhenhua W, Wenyong F, Mingyuan S (2005) Correlationship between interleukin-13 genotype and phenotype in children with bronchial asthma. J Clin Pediatr 23:312–314 in Chinese

    Google Scholar 

  28. Kim HB, Kang MJ, Lee SY, Jin HS, Kim JH, Kim BS, Jang SO, Lee YC, Sohn MH, Kim KE, Hong SJ (2008) Combined effect of tumour necrosis factor-alpha and interleukin-13 polymorphisms on bronchial hyperresponsiveness in Korean children with asthma. Clin Exp Allergy 38:774–780

    PubMed  Article  CAS  Google Scholar 

  29. Lee SG, Kim BS, Kim JH, Lee SY, Choi SO, Shim JY, Hong TJ, Hong SJ (2004) Gene-gene interaction between interleukin-4 and interleukin-4 receptor alpha in Korean children with asthma. Clin Exp Allergy 34:1202–1208

    PubMed  Article  CAS  Google Scholar 

  30. Li H, Xiaoyan D, Quanhua L, Jie L, Yixiao B (2009) Single-nucleotide polymorphisms in genes predisposing to asthma in children of Chinese Han nationality. J Investig Allergol Clin Immunol 19:391–395

    PubMed  CAS  Google Scholar 

  31. Lina L, Yuewen Z (2005) Study on Relationship between Asthma and Polymorphisms of Interleukin-4 Receptor and Interleukin-4. J Med Forum 26:38–40 in Chinese

    Google Scholar 

  32. Lin-yuan Z, Shu-guang L, Ya-wei Z, Shi-ru N, Bao-yu L, Min D, Yin-long J, Tong-zhang Z, Yu-xin Z (2010) Association between genetic polymorphism in interleukin-4 and the risk of childhood asthma. J Toxicol 6:3 in Chinese

    Article  Google Scholar 

  33. Mak JC, Ko FW, Chu CM, Leung HC, Chan HW, Cheung AH, Ip MS, Chan-Yeung M (2007) Polymorphisms in the IL-4, IL-4 receptor alpha chain, TNF-alpha, and lymphotoxin-alpha genes and risk of asthma in Hong Kong Chinese adults. Int Arch Allergy Immunol 144:114–122

    PubMed  Article  CAS  Google Scholar 

  34. Martinez FD (2007) Genes, environments, development and asthma: a reappraisal. Eur Respir J 29:179–184

    PubMed  Article  CAS  Google Scholar 

  35. Michel S, Liang L, Depner M, Klopp N, Ruether A, Kumar A, Schedel M, Vogelberg C, von Mutius E, von Berg A, Bufe A, Rietschel E, Heinzmann A, Laub O, Simma B, Frischer T, Genuneit J, Gut IG, Schreiber S, Lathrop M, Illig T, Kabesch M (2010) Unifying candidate gene and GWAS Approaches in Asthma. Plos One 5:e13894

    PubMed  Article  Google Scholar 

  36. Ming W, Hongchun S, Shujuan L (2007) Relationship between IL-13 exon 4 gene polymorphisms A2044G and the patients with asthma. Clin Med J China 14:329–330 in Chinese

    Google Scholar 

  37. Moissidis I, Chinoy B, Yanamandra K, Napper D, Thurmon T, Bocchini J Jr, Bahna SL (2005) Association of IL-13, RANTES, and leukotriene C4 synthase gene promoter polymorphisms with asthma and/or atopy in African Americans. Genet Med 7:406–410

    PubMed  Article  CAS  Google Scholar 

  38. Nagarkatti R, Kumar R, Sharma SK, Ghosh B (2004) Association of IL4 gene polymorphisms with asthma in North Indians. Int Arch Allergy Immunol 134:206–212

    PubMed  Article  CAS  Google Scholar 

  39. Noguchi E, Shibasaki M, Arinami T, Takeda K, Yokouchi Y, Kawashima T, Yanagi H, Matsui A, Hamaguchi H (1998) Association of asthma and the interleukin-4 promoter gene in Japanese. Clin Exp Allergy 28:449–453

    PubMed  Article  CAS  Google Scholar 

  40. Sandford AJ, Chagani T, Zhu S, Weir TD, Bai TR, Spinelli JJ, Fitzgerald JM, Behbehani NA, Tan WC, Pare PD (2000) Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity. J Allergy Clin Immunol 106:135–140

    PubMed  Article  CAS  Google Scholar 

  41. Schubert K, von Bonnsdorf H, Burke M, Ahlert I, Braun S, Berner R, Deichmann KA, Heinzmann A (2006) A comprehensive candidate gene study on bronchial asthma and juvenile idiopathic arthritis. Dis Markers 22:127–132

    PubMed  CAS  Google Scholar 

  42. Shirakawa I, Deichmann KA, Izuhara I, Mao I, Adra CN, Hopkin JM (2000) Atopy and asthma: genetic variants of IL-4 and IL-13 signalling. Immunol Today 21:60–64

    PubMed  Article  CAS  Google Scholar 

  43. Takabayashi A, Ihara K, Sasaki Y, Suzuki Y, Nishima S, Izuhara K, Hamasaki N, Hara T (2000) Childhood atopic asthma: positive association with a polymorphism of IL-4 receptor alpha gene but not with that of IL-4 promoter or Fc epsilon receptor I beta gene. Exp Clin Immunogenet 17:63–70

    PubMed  Article  CAS  Google Scholar 

  44. Thakkinstian A, McEvoy M, Minelli C, Gibson P, Hancox B, Duffy D, Thompson J, Hall I, Kaufman J, Leung TF, Helms PJ, Hakonarson H, Halpi E, Navon R, Attia J (2005) Systematic review and meta-analysis of the association between {beta}2-adrenoceptor polymorphisms and asthma: a HuGE review. Am J Epidemiol 162:201–211

    PubMed  Article  Google Scholar 

  45. Tianpen C, Lin W, Jianmin W, Lihua H, Jungang X (2003) Polymorphisms in IL-4 and IL-4R genes and allergic asthma in adult. Immunol J 19:454–459 (in Chinese)

    Google Scholar 

  46. van der Pouw Kraan TC, van Veen A, Boeije LC, van Tuyl SA, de Groot ER, Stapel SO, Bakker A, Verweij CL, Aarden LA, van der Zee JS (1999) An IL-13 promoter polymorphism associated with increased risk of allergic asthma. Genes Immun 1:61–65

    PubMed  Article  Google Scholar 

  47. Wang W, Halmurat W, Yilihamu S, Xiang YB, Ablikemu A (2004) A study on the relationship between interleukin-4 promoter polymorphism and asthma in a Xinjiang Uyger population. Chin J Tuberc Respir Dis 27:460–464

    Google Scholar 

  48. Wang JY, Liou YH, Wu YJ, Hsiao YH, Wu LS (2009) An association study of 13 SNPs from seven candidate genes with pediatric asthma and a preliminary study for genetic testing by multiple variants in Taiwanese population. J Clin Immunol 29:205–209

    PubMed  Article  Google Scholar 

  49. Weiss KB, Gergen PJ, Wagener DK (1993) Breathing better or wheezing worse? The changing epidemiology of asthma morbidity and mortality. Annu Rev Public Health 14:491–513

    PubMed  Article  CAS  Google Scholar 

  50. Wu B, Liu JL, Chen M, Deng RQ, Wu D (2004) Correlation of interleukin-13 gene −1112c/T polymorphism with asthma and total plasma IgE levels. Zhonghua Jie He He Hu Xi Za Zhi 27:668–671

    PubMed  Google Scholar 

  51. Wu X, Li Y, Chen Q, Chen F, Cai P, Wang L, Hu L (2010) Association and gene–gene interactions of eight common single-nucleotide polymorphisms with pediatric asthma in middle china. J Asthma 47:238–244

    PubMed  Article  CAS  Google Scholar 

  52. Xi D, Pan S, Cui T, Wu J (2004) Association between IL-13 gene polymorphism and asthma in Han nationality in Hubei Chinese population. J Huazhong Univ Sci Technolog Med Sci 24:219–222

    PubMed  Article  CAS  Google Scholar 

  53. Xiaohua Z, Xi W, Qiang C (2002) A study on the relationship between interleukin-4 promoter polymorphismand asthma in children. Chin J Pract Pediatr 17:475–477 in Chinese

    Google Scholar 

  54. Yang LF, Zhang Y, Liu QL (2010) Genetic Arg144Gln polymorphism of interleukin-13 and asthma in children. Mod Med J China 12:46–47 in Chinese

    Google Scholar 

  55. Yang XX, Li FX, Wu YS, Wu D, Tan JY, Li M (2011) Association of TGF-beta1, IL-4 and IL-13 gene polymerphisms with asthma in a Chinese population. Asian Pac J Allergy Immunol 29:273–277

    PubMed  CAS  Google Scholar 

  56. Yang H, Dong H, Dai Y, Zheng Y (2011) Association of interleukin-13 C-1112T and G+2044A polymorphisms with asthma: a meta-analysis. Respirology 16:1127–1135

    PubMed  Article  Google Scholar 

  57. Zhang J, Chen H, Hu L, Fu J, Zhang H, Chen Y (2002) Correlation between polymorphism of IL-4 and IL-10 gene promoter and childhood asthma and their impact upon cytokine expression. Natl Med J China 82:114–118

    CAS  Google Scholar 

  58. Zintzaras E (2006) Methylenetetrahydrofolate reductase gene and susceptibility to breast cancer: a meta-analysis. Clin Genet 69:327–336

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

This study was funded by the National Natural Science Foundation of China (30900413), Science Foundation of Heilongjiang Province of China (LC201024).

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No conflicts of interest, financial or otherwise, are declared by the authors.

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Correspondence to Lian-hong Jin or Shou-de Jin.

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Zhen-dong Wang, Duan Lian and Jing-ling Shen contributed equally to this study.

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Wang, Zd., Lian, D., Shen, Jl. et al. Association between the interleukin-4, interleukin-13 polymorphisms and asthma: a meta-analysis. Mol Biol Rep 40, 1365–1376 (2013). https://doi.org/10.1007/s11033-012-2180-0

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Keywords

  • IL-4
  • IL-13
  • Polymorphism
  • Asthma
  • Association