Review
Genetic determinants of pulmonary fibrosis: evolving concepts

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Summary

Interstitial lung diseases encompass a wide range of diffuse lung disorders that are often complicated by the development of pulmonary fibrosis and that can occur in isolation or in systemic diseases. In the past decade, availability of high-throughput genotyping and large collaborative clinical networks has led to the identification of many genetic variants associated with sporadic and familial fibrotic interstitial pneumonias. Susceptibility to idiopathic pulmonary fibrosis seems to involve a combination of polymorphisms related to epithelial cell injury and dysfunction and abnormal wound healing, whereas chronic inflammation seems important in the development of pulmonary fibrosis in sarcoidosis or collagen vascular diseases such as systemic sclerosis or rheumatoid arthritis; however, each of the disease-associated variants typically has a small effect and they are therefore not helpful in prediction of risk. Genetic studies have substantially expanded understanding of the pathogenesis of pulmonary fibrosis. Future challenges will be to assess how multiple susceptibility alleles interact with each other and environmental factors to determine disease risk and several different phenotypes, to define the mechanism of action and cellular pathways involving susceptibility alleles, and to identify which of the gene products and molecular mechanisms implicated in disease pathobiology are good therapeutic targets.

Section snippets

Pathogenesis of lung fibrosis

Fibrogenesis is a physiological and typically self-limiting part of the healing process in response to tissue injury.1 However, if the injury is severe or repetitive, or if the reparative process is uncontrolled, then excessive deposition of extracellular matrix components can lead to tissue overgrowth, fibrosis, and organ failure—a common outcome of fibrotic diseases that can affect many organs, including the lungs.2 Some forms of pulmonary fibrosis are associated with known environmental or

Predisposing factors

Many forms of evidence have contributed to knowledge of the role of genetic factors in the development of pulmonary fibrosis; these include the substantial variability in disease development in individuals exposed to similar concentrations of fibrogenic dusts, the widely different response to experimentally induced fibrosis in mice, and the occurrence of pulmonary fibrosis in inherited disorders with pleiotropic clinical manifestations (such as dyskeratosis congenita and Hermansky-Pudlak

Differentiation of lung fibrosis by pathogenetic mechanisms

The lung might be an important organ for the development of autoimmune diseases because it could prime pathogenic T cells before they are recruited to target organs in which they attack self-antigens and trigger autoimmunity.72 In parallel, investigators are increasingly aware of pulmonary involvement (especially fibrosis) in connective tissue diseases. Differentiation of pulmonary fibrosis associated with connective tissue diseases from that of idiopathic pulmonary fibrosis might not be

What might genetic findings mean for the pathogenesis of idiopathic pulmonary fibrosis

A growing body of evidence suggests that the development of pulmonary fibrosis is genetically determined. The question now is how genetic abnormalities identified by investigators can be incorporated in a unified pathogenetic model for idiopathic pulmonary fibrosis. Disease-associated mutations within SFTPC and SFTPA2, which are exclusively expressed by type 2 alveolar epithelial cells, point towards epithelial cell injury and loss of their reparative capacity, mediated by accumulation of

What might genetic findings mean for fibrosis in patients who do not have idiopathic pulmonary fibrosis

In connective tissue diseases and sarcoidosis, pulmonary fibrosis can develop after an exaggerated immune response and inflammation. Several aspects of fibrosis differ between patients with connective tissue diseases and sarcoidosis and those with idiopathic pulmonary fibrosis. Patients with sarcoidosis are usually younger than are those with idiopathic pulmonary fibrosis and only about 15–20% of individuals with sarcoidosis develop pulmonary fibrosis; fibrosis in patients with sarcoidosis is

What genetic findings might mean for treatment choices or clinical trial strategies

No drugs are available to specifically target the aberrant fibrogenetic process or repeated alveolar cell perturbations and to stop the inexorable disease progression of idiopathic pulmonary fibrosis. Nonetheless, the genetic associations identified so far have broadened understanding of the pathogenesis of idiopathic pulmonary fibrosis and suggest that investigators should pay more attention to alveolar epithelial cell stress, host defence, cell–cell adhesion, and telomere length when

Conclusions and future directions

In the past decade, understanding of the pathogenesis of idiopathic pulmonary fibrosis has substantially changed. Once thought to be the result of a chronic inflammatory process, the fibrotic response now seems to be driven by perturbation of alveolar epithelial cells, expansion of lung fibroblast and myofibroblast populations, and secretion of excessive amounts of extracellular matrix components, resulting in scarring and destruction of the lung architecture. Genetic factors substantially

Search strategy and selection criteria

We searched PubMed and Embase with use of the search terms “pulmonary fibrosis” or “interstitial lung disease” or “diffuse parenchymal lung diseases” or “fibrotic interstitial pneumonia”, in combination with the terms “genetics” or “genetic polymorphisms” or “genetic predisposition” or “genome-wide association studies”. We chose mostly publications from the past 5 years (Jan 2009 to Jan 2014), with an emphasis on research from the previous 12 months, but we also included highly regarded older

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