Skip to main content

Advertisement

SpringerLink
Log in

Effects of common atopy-associated amino acid substitutions in the IL-4 receptor alpha chain on IL-4 induced phenotypes

  • Original Paper
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

The human IL-4 receptor alpha chain gene (IL4R) is highly polymorphic and controversial reports have been published with respect to the association of different single nucleotide polymorphisms (SNPs) with atopy markers. Here we analyzed the functional and associational relevance of common IL4R coding SNPs. Transfection of B cell lines expressing the IL-4R variant V75+R576 did not result in enhanced IL-4 induced CD23 expression compared to cell lines expressing the wild type IL-4R alpha chain. Transfection of the IL-4R variant P503 into a murine T cell line did not influence IL-4 induced T-cell proliferation compared to wild type constructs. Analysis of six IL4R coding SNPs (I75V, E400A, C431R, S436L, S503P, Q576R) and common haplotypes (frequency ≥0.05%) in blood donors (n=300) did not indicate a significant association with elevated serum IgE level. Moreover, the most informative IL4R coding SNPs (I75V, C431R, Q576R) and related two- and three-point haplotypes (frequency ≥0.05%) were analyzed in a second, extended group of blood donors (n=689). Again, no significant association with elevated serum IgE was detectable. We conclude that common coding SNPs in the IL4R gene are unlikely to contribute significantly to increased IgE levels and variations outside the coding region may influence atopy susceptibility.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Andrews RP, Rosa LR, Daines MO, Khurana Hershey GK (2001) Reconstitution of a functional human type II IL-4/IL-13 receptor in mouse B cells: demonstration of species specificity. J Immunol 166:1716–22

    Google Scholar 

  • Becker KG (2004) The common variants/multiple disease hypothesis of common complex genetic disorders. Med Hypotheses 62:309–17

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Blaeser F, Bryce PJ, Ho N, Raman V, Dedeoglu F, Donaldson DD, Geha RS, Oettgen HC, Chatila TA (2003) Targeted inactivation of the IL-4 receptor alpha chain I4R motif promotes allergic airway inflammation. J Exp Med 198:1189–200

    Google Scholar 

  • Bottini N, Borgiani P, Otsu A, Saccucci P, Stefanini L, Greco E, Fontana L, Hopkin JM, Mao XQ, Shirakawa T (2002) IL-4 receptor alpha chain genetic polymorphism and total IgE levels in the English population: two-locus haplotypes are more informative than individual SNPs. Clin Genet 61:288–292

    Google Scholar 

  • Chomarat P, Banchereau J (1997) An update on interleukin-4 and its receptor. Eur Cytokine Netw 8:333–344

    Google Scholar 

  • Coffman RL, Lebman DA, Rothman P (1993) Mechanism and regulation of immunoglobulin isotype switching. Adv Immunol 54:229–270

    Google Scholar 

  • Colhoun HM, McKeigue PM, Davey SG (2003) Problems of reporting genetic associations with complex outcomes. Lancet 361:865–872

    Article  PubMed  Google Scholar 

  • Cookson WO, Sharp PA, Faux JA, Hopkin JM (1989) Linkage between immunoglobulin E responses underlying asthma and rhinitis and chromosome 11q. Lancet 1:1292–1295

    Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Daniels SE, Bhattacharrya S, James A, Leaves NI, Young A, Hill MR, Faux JA, Ryan GF, le Souef PN, Lathrop GM, Musk AW, Cookson WO (1996) A genome-wide search for quantitative trait loci underlying asthma. Nature 383:247–250

    Google Scholar 

  • Deichmann K, Bardutzky J, Forster J, Heinzmann A, Kuehr J (1997) Common polymorphisms in the coding part of the IL4-receptor gene. Biochem Biophys Res Commun 231:696–697

    Google Scholar 

  • Dupre D, Audrezet MP, Ferec C (2000) Atopy and a mutation in the interleukin-4 receptor gene. N Engl J Med 343:69–70

    Google Scholar 

  • Freimer N, Sabatti C (2004) The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology. Nat Genet 36:1045–1051

    Google Scholar 

  • Grimbacher B, Holland SM, Puck JM (1998) The interleukin-4 receptor variant Q576R in hyper-IgE syndrome. N Engl J Med 338:1073–1074

    Google Scholar 

  • Haagerup A, Bjerke T, Schiotz PO, Dahl R, Binderup HG, Kruse TA (2001) No linkage and association of atopy to chromosome 16 including the interleukin-4 receptor gene. Allergy 56:775–779

    Google Scholar 

  • Hackstein H, Hofmann H, Bohnert A, Bein G (1999) Definition of human interleukin-4 receptor alpha chain haplotypes and allelic association with atopy markers. Hum Immunol 60:1119–1127

    Google Scholar 

  • Hackstein H, Hecker M, Kruse S, Bohnert A, Ober C, Deichmann KA, Bein G (2001) A novel polymorphism in the 5′ promoter region of the human interleukin-4 receptor alpha-chain gene is associated with decreased soluble interleukin-4 receptor protein levels. Immunogenetics 53:264–269

    Google Scholar 

  • Hakonarson H, Wjst M (2001) Current concepts on the genetics of asthma. Curr Opin Pediatr 13:267–277

    Google Scholar 

  • Harada N, Yang G, Miyajima A, Howard M (1992) Identification of an essential region for growth signal transduction in the cytoplasmic domain of the human interleukin-4 receptor. J Biol Chem 267:22752–22758

    Google Scholar 

  • Hecker M, Bohnert A, Konig IR, Bein G, Hackstein H (2003) Novel genetic variation of human interleukin-21 receptor is associated with elevated IgE levels in females. Genes Immun 4:228–233

    Google Scholar 

  • Hershey GK, Friedrich MF, Esswein LA, Thomas ML, Chatila TA (1997) The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor. N Engl J Med 337:1720–1725

    Google Scholar 

  • Hosomi N, Fukai K, Oiso N, Kato A, Ishii M, Kunimoto H, Nakajima K (2004) Polymorphisms in the promoter of the interleukin-4 receptor alpha chain gene are associated with atopic dermatitis in Japan. J Invest Dermatol 122:843–845

    Google Scholar 

  • Howard TD, Koppelman GH, Xu J, Zheng SL, Postma DS, Meyers DA, Bleecker ER (2002) Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. Am J Hum Genet 70:230–236

    Article  CAS  PubMed  Google Scholar 

  • Idzerda RL, March CJ, Mosley B, Lyman SD, Vanden Bos T, Gimpel SD, Din WS, Grabstein KH, Widmer MB, Park LS (1990) Human interleukin 4 receptor confers biological responsiveness and defines a novel receptor superfamily. J Exp Med 171:861–873

    Google Scholar 

  • Izuhara K, Yanagihara Y, Hamasaki N, Shirakawa T, Hopkin JM (2000) Atopy and the human IL-4 receptor alpha chain. J Allergy Clin Immunol 106:S65–S71

    Google Scholar 

  • Kauppi P, Lindblad-Toh K, Sevon P, Toivonen HT, Rioux JD, Villapakkam A, Laitinen LA, Hudson TJ, Kere J, Laitinen T (2001) A second-generation association study of the 5q31 cytokine gene cluster and the interleukin-4 receptor in asthma. Genomics 77:35–42

    Google Scholar 

  • Keegan AD, Nelms K, White M, Wang LM, Pierce JH, Paul WE (1994) An IL-4 receptor region containing an insulin receptor motif is important for IL-4-mediated IRS-1 phosphorylation and cell growth. Cell 76:811–820

    Google Scholar 

  • Kruse S, Japha T, Tedner M, Sparholt SH, Forster J, Kuehr J, Deichmann KA (1999) The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha gene are associated with atopy and influence the signal transduction. Immunology 96:365–371

    Google Scholar 

  • Laker C, Stocking C, Bergholz U, Hess N, De Lamarter JF, Ostertag W (1987) Autocrine stimulation after transfer of the granulocyte/macrophage colony-stimulating factor gene and autonomous growth are distinct but interdependent steps in the oncogenic pathway. Proc Natl Acad Sci USA 84:8458–8462

    Google Scholar 

  • Lischke A, Kammer W, Friedrich K (1995) Different human interleukin-4 mutants preferentially activate human or murine common receptor gamma chain. Eur J Biochem 234:100–107

    Google Scholar 

  • Liu X, Beaty TH, Deindl P, Huang SK, Lau S, Sommerfeld C, Fallin MD, Kao WH, Wahn U, Nickel R (2004) Associations between specific serum IgE response and 6 variants within the genes IL4, IL13, and IL4RA in German children: the German Multicenter Atopy Study. J Allergy Clin Immunol 113:489–495

    Article  CAS  PubMed  Google Scholar 

  • Malerba G, Trabetti E, Patuzzo C, Lauciello MC, Galavotti R, Pescollderungg L, Boner AL, Pignatti PF (1999) Candidate genes and a genome-wide search in Italian families with atopic asthmatic children. Clin Exp Allergy 29:27–30

    Google Scholar 

  • Maniatis N, Collins A, Xu CF, McCarthy LC, Hewett DR, Tapper W, Ennis S, Ke X, Morton NE (2002) The first linkage disequilibrium (LD) maps: delineation of hot and cold blocks by diplotype analysis. Proc Natl Acad Sci USA 99:2228–2233

    Google Scholar 

  • Migliaccio C, Patuzzo C, Malerba G, Trabetti E, Galavotti R, Pescollderung L, Boner AL, Pignatti PF (2003) No linkage or association of five polymorphisms in the interleukin-4 receptor alpha gene with atopic asthma in Italian families. Eur J Immunogenet 30:349–353

    Google Scholar 

  • Mitsuyasu H, Izuhara K, Mao XQ, Gao PS, Arinobu Y, Enomoto T, Kawai M, Sasaki S, Dake Y, Hamasaki N, Shirakawa T, Hopkin JM (1998) Ile50Val variant of IL4R alpha upregulates IgE synthesis and associates with atopic asthma. Nat Genet 19:119–120

    Google Scholar 

  • Mitsuyasu H, Yanagihara Y, Mao XQ, Gao PS, Arinobu Y, Ihara K, Takabayashi A, Hara T, Enomoto T, Sasaki S, Kawai M, Hamasaki N, Shirakawa T, Hopkin JM, Izuhara K (1999) Cutting edge: dominant effect of Ile50Val variant of the human IL-4 receptor alpha-chain in IgE synthesis. J Immunol 162:1227–1231

    Google Scholar 

  • Nakamura H, Miyagawa K, Ogino K, Endo T, Imai T, Ozasa K, Motohashi Y, Matsuzaki I, Sasahara S, Hatta K, Eboshida A (2003) High contribution contrast between the genes of eosinophil peroxidase and IL-4 receptor alpha-chain in Japanese cedar pollinosis. J Allergy Clin Immunol 112:1127–1131

    Google Scholar 

  • Noben-Trauth N, Shultz LD, Brombacher F, Urban JF Jr, Gu H, Paul WE (1997) An interleukin 4 (IL-4)-independent pathway for CD4+ T cell IL-4 production is revealed in IL-4 receptor-deficient mice. Proc Natl Acad Sci USA 94:10838–10843

    Google Scholar 

  • Noguchi E, Shibasaki M, Arinami T, Takeda K, Yokouchi Y, Kobayashi K, Imoto N, Nakahara S, Matsui A, Hamaguchi H (1999a) Lack of association of atopy/asthma and the interleukin-4 receptor alpha gene in Japanese. Clin Exp Allergy 29:228–233

    Google Scholar 

  • Noguchi E, Shibasaki M, Arinami T, Takeda K, Yokouchi Y, Kobayashi K, Imoto N, Nakahara S, Matsui A, Hamaguchi H (1999b) No association between atopy/asthma and the ILe50Val polymorphism of IL-4 receptor. Am J Respir Crit Care Med 160:342–345

    Google Scholar 

  • Ober C, Leavitt SA, Tsalenko A, Howard TD, Hoki DM, Daniel R, Newman DL, Wu X, Parry R, Lester LA, Solway J, Blumenthal M, King RA, Xu J, Meyers DA, Bleecker ER, Cox NJ (2000) Variation in the interleukin 4-receptor alpha gene confers susceptibility to asthma and atopy in ethnically diverse populations. Am J Hum Genet 66:517–526

    Google Scholar 

  • Pan PY, Rothman P (1999) IL-4 receptor mutations. Curr Opin Immunol 11:615–620

    Google Scholar 

  • Patuzzo C, Trabetti E, Malerba G, Martinati LC, Boner AL, Pescollderungg L, Zanoni G, Pignatti PF (2000) No linkage or association of the IL-4Ralpha gene Q576R mutation with atopic asthma in Italian families. J Med Genet 37:382–384

    Google Scholar 

  • Risma KA, Wang N, Andrews RP, Cunningham CM, Ericksen MB, Bernstein JA, Chakraborty R, Hershey GK (2002) V75R576 IL-4 receptor alpha is associated with allergic asthma and enhanced IL-4 receptor function. J Immunol 169:1604–1610

    Google Scholar 

  • Rogala B, Rymarczyk B, Moczulski D, Grzeszczak W (2001) The role of R576Q polymorphism of interleukin-4 receptor alpha gene in atopy: results of a family-based study design. J Invest Allergol Clin Immunol 11:285–289

    Google Scholar 

  • Ryan JJ, McReynolds LJ, Keegan A, Wang LH, Garfein E, Rothman P, Nelms K, Paul WE (1996) Growth and gene expression are predominantly controlled by distinct regions of the human IL-4 receptor. Immunity 4:123–132

    Google Scholar 

  • Sasieni PD (1997) From genotypes to genes: doubling the sample size. Biometrics 53:1253–261

    Google Scholar 

  • Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434

    Article  PubMed  Google Scholar 

  • Schreiner S, Birke M, Garcia-Cuellar MP, Zilles O, Greil J, Slany RK (2001) MLL-ENL causes a reversible and myc-dependent block of myelomonocytic cell differentiation. Cancer Res 61:6480–6486

    Google Scholar 

  • Smirnova I, Mann N, Dols A, Derkx HH, Hibberd ML, Levin M, Beutler B (2003) Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc Natl Acad Sci USA 100:6075–6080

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Tan EC, Lee BW, Tay AW, Shek L, Chew FT, Tay AH (1999) Interleukin-4 receptor variant Q576R: ethnic differences and association with atopy. Clin Genet 56:333–334

    Google Scholar 

  • Thomas DC, Clayton DG (2004) Betting odds and genetic associations. J Natl Cancer Inst 96:421–423

    Google Scholar 

  • Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N (2004) Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 96:434–442

    Google Scholar 

  • Wang HY, Shelburne CP, Zamorano J, Kelly AE, Ryan JJ, Keegan AD (1999) Cutting edge: effects of an allergy-associated mutation in the human IL-4R alpha (Q576R) on human IL-4-induced signal transduction. J Immunol 162:4385–4389

    Google Scholar 

  • Wills-Karp M, Ewart SL (2004) Time to draw breath: asthma-susceptibility genes are identified. Nat Rev Genet 5:376–387

    Google Scholar 

  • Wjst M, Kruse S, Illig T, Deichmann K (2002) Asthma and IL-4 receptor alpha gene variants. Eur J Immunogenet 29:263–268

    Google Scholar 

Download references

Acknowledgements

We thank all the individuals who participated in our study. We acknowledge the excellent technical assistance of Ms. Andrea Debus, Ms. Gabriela Haley, Ms. Angelika Nockher and Ms. Uta Schellenberg. The experiments comply with the current laws of Germany. This work was supported by grants from the Bundesministerium für Bildung und Forschung, Germany (NGFN IE-S08T03, GE-S13T01) and the Deutsche Forschungsgemeinschaft (SFB 466, B10)

Author information

Authors and Affiliations

  1. Institute of Clinical Immunology and Transfusion Medicine, Justus Liebig University, Langhansstrasse 7, 35392, Giessen, Germany

    Izolda Franjkovic, Karin Kissel, Anette Bohnert, Anne Hartung, Astrid Ohly, Holger Hackstein & Gregor Bein

  2. Institute of Clinical Microbiology, Immunology and Hygiene, University of Erlangen, 91054, Erlangen, Germany

    Andre Gessner

  3. Institute of Medical Biometry and Statistics, University of Lübeck, 23554, Lübeck, Germany

    Inke König & Andreas Ziegler

Authors
  1. Izolda Franjkovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andre Gessner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Inke König
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karin Kissel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anette Bohnert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anne Hartung
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Astrid Ohly
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andreas Ziegler
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Holger Hackstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gregor Bein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Izolda Franjkovic.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Franjkovic, I., Gessner, A., König, I. et al. Effects of common atopy-associated amino acid substitutions in the IL-4 receptor alpha chain on IL-4 induced phenotypes. Immunogenetics 56, 808–817 (2005). https://doi.org/10.1007/s00251-004-0763-1

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-004-0763-1

Keywords

Search

Navigation