title: Function associated transforming growth factor-beta gene polymorphism in chronic beryllium disease.
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 beta 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) beta(1) genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-beta(1) (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-beta(1) (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-beta(1) (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-beta(1) (codon 25) PM genotype frequency associated with a low TGF-beta release suggests that immunoregulatory cytokines such as TGF-beta 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-alpha and TGF-beta(1), 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.
authors.affiliation: Medical University Hospital Freiburg, Department of Pneumology, Killianstrasse 5, 79106 Freiburg, Germany. kgaede@fz-borstel.de
authors.forename: Karoline I
authors.initials: KI
authors.lastname: Gaede
authors.forename: Massimo
authors.initials: M
authors.lastname: Amicosante
authors.forename: Manfred
authors.initials: M
authors.lastname: Schürmann
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Fireman
authors.forename: Cesare
authors.initials: C
authors.lastname: Saltini
authors.forename: Joachim
authors.initials: J
authors.lastname: Müller-Quernheim
mesh_terms: D000328:Adult; D000483:Alleles; D001607:Berylliosis / Q000175:diagnosis / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D002908:Chronic Disease; D003062:Codon; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005858:Germany; D006682:HLA-DP Antigens / Q000235:genetics / Q000378:metabolism; D059868:HLA-DP beta-Chains; D006683:HLA-DQ Antigens / Q000235:genetics / Q000378:metabolism; D059866:HLA-DQ beta-Chains; D006801:Humans; D007557:Israel; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014481:United States
chemical_list: D003062:Codon; D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C071170:HLA-DPB1 antigen; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha