Recent advances in genetic predisposition to clinical acute lung injury

Abstract

It has been well established that acute lung injury (ALI), and the more severe presentation of acute respiratory distress syndrome (ARDS), constitute complex traits characterized by a multigenic and multifactorial etiology. Identification and validation of genetic variants contributing to disease susceptibility and severity has been hampered by the profound heterogeneity of the clinical phenotype and the role of environmental factors, which includes treatment, on outcome. The critical nature of ALI and ARDS, compounded by the impact of phenotypic heterogeneity, has rendered the amassing of sufficiently powered studies especially challenging. Nevertheless, progress has been made in the identification of genetic variants in select candidate genes, which has enhanced our understanding of the specific pathways involved in disease manifestation. Identification of novel candidate genes for which genetic association studies have confirmed a role in disease has been greatly aided by the powerful tool of high-throughput expression profiling. This article will review these studies to date, summarizing candidate genes associated with ALI and ARDS, acknowledging those that have been replicated in independent populations, with a special focus on the specific pathways for which candidate genes identified so far can be clustered.

Fig. 1.

Networks revealed through the Ingenuity Pathways Analysis based on 21 ALI genes established in acute lung injury genetic association studies. The major network of 36 genes (the 12 published ALI genes are highlighted in blue) was merged with the second network of 35 genes (the 9 genes previously associated with ALI are highlighted in green). Molecules highlighted in gray represent molecules that belong to a group (multiple specific molecules with a similar function) or a protein complex made up of multiple protein subunits in the network. Genes/molecules are connected according to their relationships, and the newly added relationships that connect the two networks are also highlighted in orange. The top 5 diseases/disorders related to genes/molecules in the two networks include 1) organismal injury and abnormalities; 2) immunological disease; 3) hematological disease; 4) respiratory disease; and 5) inflammatory disease. Top molecular and cellular functions suggested by the networks are cellular movement, cell death, lipid metabolism, small molecule biochemistry, and cell-to-cell signaling and interaction.