Insights from human genetic studies of lung and organ fibrosis
Christine Kim Garcia
Christine Kim Garcia
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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.

Authors

Christine Kim Garcia

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Figure 2

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

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Cascade of maladaptive responses originating from inherited genetic vari...
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.