Journal of Molecular Medicine

, Volume 83, Issue 5, pp 397–405 | Cite as

Function associated transforming growth factor-β gene polymorphism in chronic beryllium disease

  • Karoline I. Gaede
  • Massimo Amicosante
  • Manfred Schürmann
  • Elisabeth Fireman
  • Cesare Saltini
  • Joachim Müller-Quernheim
Original Article

Abstract

Chronic beryllium disease (CBD) is a rare occupational, granulomatous lung disease clinically resembling sarcoidosis. The immune response to beryllium is thought to depend on genetic susceptibility. Although a glutamic acid in position 69 of the human leukocyte antigen-DP β chain (HLA-DPB1-Glu69) is associated with the development of CBD, it cannot fully explain susceptibility. It is likely that additionally other genes are involved in regulating the immune and inflammatory response in the pathogenesis of this disease. Functional gene polymorphisms (PMs) of the tumor necrosis factor (TNF)A and transforming growth factor (TGF) β1 genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-β1 (codon 25) PM in 59 patients with CBD and 164 matched healthy controls, from two groups of European/Israeli and United States origin. Additionally, patients were genotyped for HLA class II gene variants and the TNFA (−308) PM. The most significant results were found for the TGF-β1 (codon 25) PM with a shift towards the low producing non-GG genotypes in the subgroup of European and Israeli patients with CBD (62.50% vs. 13.82% in healthy controls; P<0.001). This phenomenon was not observed in the group from the United States. Moreover, TGF-β1 (codon 25) PM genotype frequencies from United States CBD patients differed significantly from those of European and Israeli patients. In contrast, increased frequencies for the high producing TNFA2 allele were found only in the patients from the United States (28.20% vs. 8.96% in healthy controls; P<0.005) but not in the group of Europe and Israel. In conclusion, the increase in TGF-β1 (codon 25) PM genotype frequency associated with a low TGF-β release suggests that immunoregulatory cytokines such as TGF-β are involved in the pathogenesis of CBD. Moreover, based on the interaction of gene PMs associated with the control of the immune response, such as TNF-α and TGF-β1, with a specific immune response gene such as HLA-DPB1-Glu69 or other HLA-class II PMs driving the immune response to Be, the present data suggest that a combination of different genetic backgrounds determine susceptibility for the same immunopathological reaction and disease.

Keywords

Chronic beryllium disease TGF-β gene polymorphism TNFA-HLA 

Abbreviations

BAL

Bronchoalveolar lavage

BH

Beryllium hypersensitivity

CBD

Chronic beryllium disease

TGF

Transforming growth factor

TNF

Tumor necrosis factor

Notes

Acknowledgements

The authors thank Stefanie Adam and Carmen Schöne for expert technical assistance. This study was supported in part by the German Research Council (DFG, Mu 692-3/3), the United States Department of Energy (grant DE-FG02-93ER61714 and DE-FG02-ER63416), and a grant from the Guzzini Foundation. Major parts of this study were performed in the Medical Hospital of the Research Center, Borstel, Germany.

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Karoline I. Gaede
    • 1
    • 2
  • Massimo Amicosante
    • 3
  • Manfred Schürmann
    • 4
  • Elisabeth Fireman
    • 5
  • Cesare Saltini
    • 3
  • Joachim Müller-Quernheim
    • 1
  1. 1.Medical University Hospital FreiburgDepartment of PneumologyFreiburgGermany
  2. 2.Research Center BorstelBorstelGermany
  3. 3.Department of Internal MedicineUniversity of Rome Tor VergataRomeItaly
  4. 4.Institute of Human GeneticsUniversity LübeckLübeckGermany
  5. 5.Tel Aviv Sourasky Medical CenterDepartment of Pulmonary and Allergic Diseases

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