Genetic susceptibility in pneumoconiosis☆
Introduction
In contrast to mutations, common allelic variants are present in high frequencies (>1%) in the general population. Among these variants, the most represented type of variations is single nucleotide substitutions, referred to as single nucleotide polymorphisms (SNPs). “Susceptibility profiles” reflecting the combined influence of multiple common risk alleles defines inter-individual variability due to genetics in the population. Common variants generally possess low or incomplete penetrance, interact with other genes or environment and consequently show low risk associations in epidemiological studies (e.g., odd ratios ∼ 1.5 – 2). Functional variants that affect phenotype are believed to contribute to the risk of common polygenic diseases, and this has led to the common disease-common variant (CD-CV) hypothesis. Several examples of well established associations between common variants and common diseases include APOE*E4 and Alzheimer's disease (Saunders et al., 1993), CCR5Δ32 and resistance to HIV infection (Dean et al., 1996) and α1-antitrypsin (AAT) deficiency and chronic obstructive pulmonary disease (COPD) (Poller et al., 1990).
Although genetic association studies help to uncover the contribution of genetic background in disease susceptibility and severity, complex interplay between genetic and environmental factors creates a challenge in understanding the etiology of complex diseases. Environmental epidemiology using genetic information has focused primarily on examining hypothesis-driven associations between environmental/occupational diseases and specific polymorphisms such as silicosis and TNFα-308 (Yucesoy et al., 2001b), chronic beryllium disease and HLA-DP Glu69 (Lombardi et al., 2001, McCanlies et al., 2004) in well characterized populations. Genetic modifiers are known for a number of common complex diseases where immune/inflammatory mediators and environmental factors play a role. This review summarizes the results of recent studies on the associations of common gene variants with pulmonary fibrosis, with a specific focus on occupationally exposed populations.
Section snippets
Genes involved in chronic inflammatory/fibrotic lung diseases
The pathogenesis of fibrotic lung diseases involve activation of inflammatory cells, fibroblast cell proliferation and the enhanced synthesis and/or breakdown of extracellular matrix components (Borm and Schins, 2001). Cytokines, chemokines, and growth factors play a crucial role in the onset, progression and termination of these reactions. Here, representative mediators whose genetic variants implicated in the development/progression or severity of fibrotic lung diseases are described.
The
Genetic associations in pneumoconiotic diseases
Although many candidate genes are known to be involved in the pathogenesis of pulmonary fibrosis, only a limited number of their variants have been evaluated to date for associations. Most genetic association studies have focused on polymorphisms in the IL-1 and TNF gene families, however, chemokines, HLA and antioxidant gene variations have been examined to some extent.
Gene–gene, gene–environment interactions
As with other complex diseases, several gene–gene interactions may exist in pneumoconiosis. In silicosis, the presence of both IL-1α + 4845 and TNFα-238 variants was associated with decreased odds of moderate disease. The association between TNFα-238 and severe silicosis was greater in subjects without the IL-1α variant. A second interaction was found between IL-1RA + 2018 and TNFα-308 variants. The proportion of moderate cases increased independently with the presence of either minor variant. For
Conclusion
Genetic epidemiology offers a powerful approach to the identification of genetic variants that influence susceptibility to many multifactorial diseases. Although the pathogenesis of pulmonary fibrosis remains incompletely understood, identification and understanding the role of genetic risk factors help provide novel insights into etiology of the disease and helps to identify molecular regulators of inflammatory and fibrotic processes in the lung. In spite of some contradictory findings in
References (58)
- et al.
TGF-beta and fibrosis
Microbes Infect.
(1999) - et al.
Beryllium exposure and chronic beryllium disease
Lancet
(2004) - et al.
Polymorphisms in chemokine and chemokine receptor genes and the development of coal workers’ pneumoconiosis
Cytokine
(2006) - et al.
Production of collagenase and tissue inhibitor of metalloproteinases by fibroblasts derived from normal and fibrotic human lungs
Chest
(1992) - et al.
Interleukin 1 receptor antagonist (IL-1ra) prevents or cures pulmonary fibrosis elicited in mice by bleomycin or silica
Cytokine
(1993) - et al.
Dose-dependent induction of transforming growth factor beta (TGF-beta) in the lung tissue of fibrosis-prone mice after thoracic irradiation
Int. J. Radiat. Oncol. Biol. Phys.
(2000) - et al.
Mechanisms and mediators in coal dust induced toxicity: a review
Ann. Occup. Hyg.
(1999) - et al.
Effect of IL-6 on alveolar fibroblast proliferation in interstitial lung diseases
Clin. Immunol. Immunopathol.
(1996) - et al.
Inflammatory and immunomodulatory roles of TGF-beta
Immunol. Today
(1989) - et al.
Association of tumor necrosis factor-alpha and interleukin-1 gene polymorphisms with silicosis
Toxicol. Appl. Pharmacol.
(2001)
Matrix metalloproteinase-9 in lung remodeling
Am. J. Respir. Cell. Mol. Biol.
PCR analysis of cytokine induction profiles associated with mouse strain variation in susceptibility to pulmonary fibrosis
Reg. Immunol.
Genotype and phenotype in susceptibility to coal workers’ pneumoconiosis. The use of cytokines in perspective
Eur. Respir. J.
Polymorphisms in the tumor necrosis factor-alpha gene promoter may predispose to severe silicosis in black South African miners
Am. J. Respir. Crit. Care Med.
Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study
Science
Localization of matrix metalloproteinases-1, -2, and -9 and tissue inhibitor of metalloproteinase-2 in interstitial lung diseases
Lab. Invest.
Function associated transforming growth factor-beta gene polymorphism in chronic beryllium disease
J. Mol. Med.
Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF
Eur. Respir. J.
Immunogenetic analysis of silicosis in Japan
Am. J. Respir. Cell. Mol. Biol.
Immunohistochemical localization of transforming growthfactor beta isoforms in asbestos-related diseases
Environ. Health Perspect.
TGF-beta 1, but not TGF-beta 2 or TGF-beta 3, is differentially present in epithelial cells of advanced pulmonary fibrosis: an immunohistochemical study
Am. J. Respir. Cell. Mol. Biol.
Tumor necrosis factor-alpha gene promoter polymorphism in coal workers’ pneumoconiosis.
Mol. Cell. Biochem.
Molecular mechanisms of pulmonary fibrosis and current treatment
Curr. Mol. Med.
Polymorphisms in the CD14 gene associated with pulmonary function in farmers
Am. J. Respir. Crit. Care Med.
Up-regulated expression of transforming growth factor-alpha in the bronchiolar-alveolar duct regions of asbestos-exposed rats
Am. J. Pathol.
HLA-DP allele-specific T cell responses to beryllium account for DP-associated susceptibility to chronic beryllium disease
J. Immunol.
Influence of MHC class II in susceptibility to beryllium sensitization and chronic beryllium disease
J. Immunol.
Angiotensin-1 converting enzyme polymorphisms in chronic beryllium disease
Am. J. Respir. Crit. Care Med.
High beryllium-stimulated TNF-alpha is associated with the -308 TNF-alpha promoter polymorphism and with clinical severity in chronic beryllium disease
Am. J. Respir. Crit. Care Med.
Cited by (45)
The rs2609255 polymorphism in the FAM13A gene is reproducibly associated with silicosis susceptibility in a Chinese population
2018, GeneCitation Excerpt :The cause of silicosis is relatively unitary in that occupational inhalation of free crystalline silicon dioxide or silica is considered the primary aetiological factor (Leung et al., 2012). However, individual variation in susceptibility to silicosis is observed even if workers are exposed to similar amounts of silica dust at a given time (Yucesoy and Luster, 2007). With the rapid development of genotyping technologies such as genome-wide association studies (GWASs) and next-generation sequencing (NGS), our understanding of the genetic factors (mainly single-nucleotide polymorphisms, SNPs) that confer silicosis risk has substantially expanded (Chu et al., 2014).
Genetic susceptibility to toxicologic lung responses among inbred mouse strains following exposure to carbon nanotubes and profiling of underlying gene networks
2017, Toxicology and Applied PharmacologyCitation Excerpt :Genetic factors are thought and often shown to modify the risk of toxic responses of the respiratory system in animal models including chronic inflammation, fibrosis, airway hypersensitivity, cardiovascular complications, and carcinogenesis (Kleeberger, 2005; Peden, 2005). Concurrently, there are many studies which support roles for genetic factors in the risk of coal worker's pneumoconiosis, farmer's lung disease, silicosis, fibrosing alveolitis (idiopathic pulmonary fibrosis), asbestosis, and malignant mesothelioma (Hirvonen et al., 1995; Honda et al., 1993; Yucesoy and Luster, 2007). In particular, there has been interest in identifying genetic factors which may determine risk of malignant mesothelioma among asbestos-exposed human populations, however this has proven difficult to demonstrate due to large numbers of confounding factors (such as co-exposures) and small sample sizes (Horská et al., 2006; Neri et al., 2008).
Pathway analysis for a genome-wide association study of pneumoconiosis
2015, Toxicology LettersCitation Excerpt :As a consequence of long-term dust exposure, there is increased mortality due to respiratory diseases, lung cancer, and cardiovascular disease (Chen et al., 2012). Although environmental factors are prominent in the pathogenesis of pneumoconiosis, a genetic component of susceptibility has been established (Yucesoy and Luster, 2007). Previous studies using candidate gene approaches have discovered, within genes, single-nucleotide polymorphisms (SNPs) that are associated with susceptibility to pneumoconiosis.
Pneumoconioses
2015, Murray and Nadel's Textbook of Respiratory Medicine: Volume 1,2, Sixth EditionGITR promoter polymorphism contributes to risk of coal workers' pneumoconiosis: A case-control study from China
2014, Immunology LettersCitation Excerpt :However, only a weak association was detected between CWP and the rs2298213 polymorphisms in the additive model. CWP is generally considered as a chronic and persistent inflammatory lung disease which was involved in complex environmental and genetic factors [3,30]. Genetic factors can influence the susceptibility and/or severity of CWP.
- ☆
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health.