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1 Variants in Chronic Beryllium Disease and Sarcoidosis1
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* Robert H. Hollis Laboratory of Environmental and Occupational Health, Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206;
Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262;
Division of Pulmonary and Critical Care Sciences, Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, CO 80262; and
Clinical Genomic Group, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, United Kingdom
Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-
1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-1 variants or haplotypes. The –509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the –509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the –509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the –509C and codon 10T, implicated in lower levels of TGF-1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-1, although future studies will be needed to correlate TGF-1 protein levels with known TGF-1 genotypes and assess whether there is a shared mechanisms for TGF-1 in these two granulomatous diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by P01 ES11810 and M01 RR00051 from the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Lisa A. Maier, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail address: maierL{at}njc.org
3 A list of members of The ACCESS Group appears in Acknowledgments.
4 Abbreviations used in this paper: CBD, chronic beryllium disease; SNP, single nucleotide polymorphism; BeLPT, beryllium lymphocyte proliferation test; BAL, bronchoalveolar lavage; FEV1, forced expiratory volume in 1 s; FVC, forced expiratory vital capacity; TLC, total lung capacity; DLCO, diffusion capacity of carbon monoxide; CI, confidence interval; OR, odds ratio; IPF, idiopathic pulmonary fibrosis.
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