Abstract
The etiology of inflammatory diseases of the lung like sarcoidosis and chronic obstructive pulmonary disease (COPD) is multifactorial. The main trigger for developing a COPD is tobacco smoking while exogenous factors causing sarcoidosis are unclear. In both diseases there is an underlying genetic susceptibility determining both the onset and the course of the diseases. Toll-like receptor (TLR)-9 plays an important role in innate immunity by recognizing bacterial CpG-DNA motifs. It is unclear whether single nucleotide polymorphisms (SNPs) in TLR-9 are able to alter the course of sarcoidosis or COPD, or raise the susceptibility for developing one of the disorders. We examined two SNPs in the promoter region of the TLR-9 gene (T1486C and T1237C) in 175 COPD patients (59% with a stable course of the disease, 41% with an instable course with more than 3 exacerbations over the last 3 years) and 166 sarcoidosis patients (19% with an acute and 81% with a chronic course of the disease lasting >2 years) comparing each group to 233 healthy controls. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis was used for genotyping. The C-allele frequency of T1486C was significantly elevated in COPD patients (p = 0.008). For T1237C there were no significant associations comparing the COPD cohort with the controls. In the sarcoidosis cohort, we could observe a significantly higher prevalence of the C-allele for T1237C in the chronic sarcoidosis cohort in comparison to the control group (p = 0.026). For T1486 there no statistical association was observed. This is the first study showing an association between a SNP (T1486C) in the TLR-9 gene and the onset of COPD. Moreover, we could demonstrate that T1237C is able to alter the course of sarcoidosis as a disease-modifying gene. This study underlines that SNPs in TLR-9 might be involved in acquiring and maintaining lung diseases such as sarcoidosis and COPD.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Berghöfer, B., Frommer, T., König, I. R., Ziegler, A., Chakraborty, T., Bein, G., & Hackstein, H. (2005). Common human Toll-like receptor 9 polymorphisms and haplotypes: Association with atopy and functional relevance. Clinical and Experimental Allergy, 35, 1147–1154.
Celli, B. R., & MacNee, W. (2004). ATS/ERS Task force. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. European Respiratory Journal, 23, 932–946.
Chiffoleau, E., Heslan, J. M., Heslan, M., Louvet, C., Condamine, T., & Cuturi, M. C. (2007). TLR9 ligand enhances proliferation of rat CD4+ T cell and modulates suppressive activity mediated by CD4+ CD25+ T cell. International Immunology, 19, 193–201.
Drent, M., van den Berg, R., Haenen, G. R., van den Berg, H., Wouters, E. F., & Bast, A. (2001). NF-kappaB activation in sarcoidosis. Sarcoidosis, Vasculitis, and Diffuse Lung Diseases, 18, 50–56.
Elmaagacli, A. H., Koldehoff, M., & Beelen, D. W. (2009). Improved outcome of hematopoietic SCT in patients with homozygous gene variant of Toll-like receptor 9. Bone Marrow Transplantation, 44, 295–302.
Hayashi, F., Means, T. K., & Luster, A. D. (2003). Toll-like receptors stimulate human neutrophil function. Blood, 102, 2660–2669.
Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., Matsumoto, M., Hoshino, K., Wagner, H., Takeda, K., & Akira, S. (2000). A Toll-like receptor recognizes bacterial DNA. Nature, 408, 740–745.
Iannuzzi, M. C., Rybicki, B. A., & Teirstein, A. S. (2007). Sarcoidosis. The New England Journal of Medicine, 357, 2153–2165.
Isajevs, S., Taivans, I., Svirina, D., Strazda, G., & Kopeika, U. (2011). Patterns of inflammatory responses in large and small airways in smokers with and without chronic obstructive pulmonary disease. Respiration, 81, 362–371.
Juarez, E., Nuñez, C., Sada, E., Ellner, J. J., Schwander, S. K., & Torres, M. (2010). Differential expression of Toll-like receptors on human alveolar macrophages and autologous peripheral monocytes. Respiratory Research, 11, 2.
Lazarus, R., Klimecki, W. T., Raby, B. A., Vercelli, D., Palmer, L. J., Kwiatkowski, D. J., Silverman, E. K., Martinez, F., & Weiss, S. T. (2003). Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): Frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies. Genomics, 81, 85–91.
Mayer, A. K., Muehmer, M., Mages, J., Gueinzius, K., Hess, C., Heeg, K., Bals, R., Lang, R., & Dalpke, A. H. (2007). Differential recognition of TLR-dependent microbial ligands in human bronchial epithelial cells. Journal of Immunology, 178, 3134–3142.
McCloskey, S. C., Patel, B. D., Hinchliffe, S. J., Reid, E. D., Wareham, N. J., & Lomas, D. A. (2001). Siblings of patients with severe chronic obstructive pulmonary disease have a significant risk of airflow obstruction. American Journal of Respiratory and Critical Care Medicine, 164, 1419–1424.
Miller, S. A., Dykes, D. D., & Polesky, H. F. (1988). A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Research, 16, 1215.
Mortaz, E., Adcock, I. M., Ito, K., Kraneveld, A. D., Nijkamp, F. P., & Folkerts, G. (2010). Cigarette smoke induces CXCL8 production by human neutrophils via activation of TLR9 receptor. European Respiratory Journal, 36, 1143–1154.
Murray, C., & Lopez, A. (1997). Mortality by cause for eight regions of the world: Global burden of disease study. Lancet, 349, 1269–1276.
Ng, M. T., Van’t Hof, R., Crockett, J. C., Hope, M. E., Berry, S., Thomson, J., McLean, M. H., McColl, K. E., El-Omar, E. M., & Hold, G. L. (2010). Increase in NF-kappaB binding affinity of the variant C allele of the toll-like receptor 9–1237T/C polymorphism is associated with Helicobacter pylori-induced gastric disease. Infection and Immunity, 78, 1345–1352.
Novak, N., Yu, C. F., Bussmann, C., Maintz, L., Peng, W. M., Hart, J., Hagemann, T., Diaz-Lacava, A., Baurecht, H. J., Klopp, N., Wagenpfeil, S., Behrendt, H., Bieber, T., Ring, J., Illig, T., & Weidinger, S. (2007). Putative association of a TLR9 promoter polymorphism with atopic eczema. Allergy, 62, 766–772.
Pellegrino, R., Viegi, G., Brusasco, V., Crapo, R. O., Burgos, F., Casaburi, R., Coates, A., van der Grinten, C. P., Gustafsson, P., Hankinson, J., Jensen, R., Johnson, D. C., MacIntyre, N., McKay, R., Miller, M. R., Navajas, D., Pedersen, O. F., & Wanger, J. (2005). Interpretive strategies for lung function tests. European Respiratory Journal, 26, 948–968.
Sandford, A., & Pare, P. (2000). Genetic risk factors for chronic obstructive pulmonary disease. Clinics in Chest Medicine, 21, 633–643.
Schurmann, M., Reichel, P., Muller-Myhsok, B., Schlaak, M., Muller-Quernheim, J., & Schwinger, E. (2001). Results from a genome-wide search for predisposing genes in sarcoidosis. American Journal of Respiratory and Critical Care Medicine, 164, 840–846.
Statement on sarcoidosis. (1999). Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee. American Journal of Respiratory and Critical Care Medicine, 160, 736–755.
Tao, K., Fujii, M., Tsukumo, S., Maekawa, Y., Kishihara, K., Kimoto, Y., Horiuchi, T., Hisaeda, H., Akira, S., Kagami, S., & Yasutomo, K. (2007). Genetic variations of Toll-like receptor 9 predispose to systemic lupus erythematosus in Japanese population. Annals of the Rheumatic Diseases, 66, 905–909.
Veltkamp, M., Van Moorsel, C. H., Rijkers, G. T., Ruven, H. J., Van Den Bosch, J. M., & Grutters, J. C. (2010). Toll-like receptor (TLR)-9 genetics and function in sarcoidosis. Clinical and Experimental Immunology, 162, 68–74.
Acknowledgments
We thank Martina Lennarz for her excellent technical support and all participants for making this study possible.
Conflicts of interest: The authors declare no conflicts of interest in relation to this article.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media Dordrecht
About this paper
Cite this paper
Pabst, S., Bradler, O., Gillissen, A., Nickenig, G., Skowasch, D., Grohe, C. (2013). Toll-Like Receptor-9 Polymorphisms in Sarcoidosis and Chronic Obstructive Pulmonary Disease. In: Pokorski, M. (eds) Respiratory Regulation - The Molecular Approach. Advances in Experimental Medicine and Biology, vol 756. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4549-0_30
Download citation
DOI: https://doi.org/10.1007/978-94-007-4549-0_30
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-4548-3
Online ISBN: 978-94-007-4549-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)