Insights from human genetic studies of lung and organ fibrosis

Abstract

Genetic investigations of fibrotic diseases, including those of late onset, often yield unanticipated insights into disease pathogenesis. This Review focuses on pathways underlying lung fibrosis that are generalizable to other organs. Herein, we discuss genetic variants subdivided into those that shorten telomeres, activate the DNA damage response, change resident protein expression or function, or affect organelle activity. Genetic studies provide a window into the downstream cascade of maladaptive responses and pathways that lead to tissue fibrosis. In addition, these studies reveal interactions between genetic variants, environmental factors, and age that influence the phenotypic spectrum of disease. The discovery of forces counterbalancing inherited risk alleles identifies potential therapeutic targets, thus providing hope for future prevention or reversal of fibrosis.

Figure 1. Genetic variants define an inherited susceptibility to pulmonary fibrosis and to different manifestations of organ fibrosis.

Genes linked to an inherited risk of pulmonary fibrosis can be broadly classified into those that lead to a DNA damage response, those that are expressed in lung epithelium, and those that are expressed in lamellar bodies — or organelles crucial for type II alveolar epithelial cell function. Examples of other manifestations of organ fibrosis using this same broad classification scheme of variants affecting DNA, protein, and organelle function are indicated to the right. Genetic disorders characterized by the involvement of multiple different organs are listed with each panel.

Figure 2. Cascade of maladaptive responses originating from inherited genetic variants and leading to tissue fibrosis.

The process of fibrosis involves many different cell types, ultimately resulting in activation of myofibroblasts, deposition of extracellular matrix proteins, aberrant remodeling, and organ failure. Regardless of underlying pathogenic variant, fibrosis results from activation of a number of different downstream maladaptive responses. These involve both cell-autonomous changes within cells directly affected by the mutation and nonautonomous changes in cells affected by perturbations in cell signaling or the extracellular milieu. Even if only a restricted population of cells is affected by the pathogenic variant(s), its effects may spill over into overlapping and interacting mechanisms of cell injury, inflammation, and fibrosis.

Figure 3. Distribution of phenotypic variation implicates multiple different alleles and roles of environment and aging.

Extreme phenotypes, such as those that are seen in patients with Mendelian disorders, occur with an earlier onset and demonstrate more rapid progression. Individuals with familial aggregation of fibrosis phenotypes show not only enrichment of pathogenic rare variants, but also effects from common variants. Environmental factors influence the spectrum of phenotypes and include direct physical or cellular injury, infection, inflammation, and nutritional effects. Aging likely influences fibrosis through genomic-independent and -dependent mechanisms. Protective genetic variants are uncommonly identified but provide information regarding forces that balance disease susceptibility factors.