The presence of well-established common genetic variants as well as rare variants within the TERT and RTEL1 genes may significantly increase the risk of developing idiopathic pulmonary fibrosis (IPF), according to a recent study in the American Journal of Respiratory and Critical Care Medicine.

This was the first whole-genome sequencing study that examined rare variant associations outside of the exome as part of the National Institutes of Health (NIH) Trans-Omics for Precision Medicine (TOPMed) Program.

For the purpose of this research, the authors collected DNA samples from eligible patients with IPF and performed whole-genome sequencing analysis. The results were compared with a selection of out-of-study healthy individuals recruited from other TOPMed program study populations.


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Association testing examined the aggregated effect of rare variants within genes or regions and discovered influential individual variants within genes. Moreover, the study researchers also estimated the heritability of IPF based on rare and common variants.

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According to the results, rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the genes consistently impacted the aggregated test statistics.

“Our common variant analysis highlights the importance of telomerase maintenance, host defense, and cell-cell adhesion genes in the development of IPF, and our overall analysis estimated IPF heritability to be 32%,” Peljto and colleagues wrote.

In addition, the whole-genome sequence analysis did not indicate any association of rare variants identified in more focused studies of familial pulmonary fibrosis, including TERC, the surfactant protein genes, TINF2, and ABCA3, with an increased overall risk of developing IPF.

The authors added: “Although additional exceedingly rare variants may prove to be risk factors in unique families or relevant to specific IPF subtypes, given their frequency, these rare variants will only influence risk for a very small proportion of the IPF population”.

Reference

Peljto AL, Blumhagen RZ, Walts AD, et al. Idiopathic pulmonary fibrosis is associated with common genetic variants and limited rare variants. Am J Respir Crit Care Med. Published online January 5, 2023. doi:10.1164/rccm.202207-1331OC