Elsevier

Toxicology Letters

Volume 168, Issue 3, 5 February 2007, Pages 249-254
Toxicology Letters

Genetic susceptibility in pneumoconiosis

https://doi.org/10.1016/j.toxlet.2006.10.021Get rights and content

Abstract

A large number of cellular mediators such as cytokines, antioxidants and growth factors have been implicated in the pathogenesis of chronic inflammatory and fibrotic diseases. Common functional polymorphisms in these genes have been shown to influence individual susceptibility to these diseases. Silicosis, coal worker pneumoconiosis, progressive massive fibrosis and berylliosis are examples of fibrotic pneumoconiosis and are characterized by irreversible fibrotic lesions in the lung resulting from chronic dust inhalation. Although the materials are the major contributory factors of the disease pathogenesis, not all individuals exposed to similar levels develop disease. This suggests that there is a genetic predisposition to their development. Therefore, an understanding of genetic variability and the interaction between genetic and environmental factors is crucial to the identification of high-risk individuals and prevention and treatment of these diseases.

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

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    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.

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