A multi-institutional, large-scale meta-analysis identified 7 novel genome-wide significant loci in patients with idiopathic pulmonary fibrosis (IPF), many of which were associated with lung function and different organ manifestations.

“Leveraging global multi-ancestry analysis further elucidates the genetic background of IPF by both revealing novel loci and providing increased resolution into previously identified ones,” the authors wrote in Cell Genomics.

Of the 7 novel loci, 4 were mostly driven by non-European ancestry. One locus driven by an intronic variant of the PSKH1 gene was only found in the East Asian population. According to the authors, these results highlight the importance of multi-ancestry analysis to identify IPF-associated loci, otherwise only 1 locus had reached genome-wide significance if only the European populations were analyzed.


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Three of the 7 novel loci were associated with forced expiratory volume in 1 second and forced vital capacity. These included the FKBP5, GPR157, and RAPGEF2 variants. Previous studies have shown that FKBP5 plays an important role in lung fibrinogenesis, while RAPGEF2 may be a risk factor for both IPF and chronic obstructive pulmonary disease. The other 4 loci have been implicated in body mass index.

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Moreover, the study found a shared genetic background between IPF and COVID-19. The researchers identified 7 variants (of 25 IPF index variants) as potentially relevant for COVID-19 hospitalization, in particular, the CRHR1, MUC5B, and DPP9 variants. MUC5B, the strongest IPF risk locus, seems to have a protective role against severe COVID-19 and has been associated with IPF patient survival.

The authors observed a 1.6 times larger effect of MUC5B in males compared with females. However, this sex-stratified effect could be a result of confounding factors and thus should be considered with caution. In addition, they observed a 2-fold higher effect size estimate in IPF clinical cohorts compared with biobanks.

This meta-analysis enrolled 11,160 patients, a number over 4-fold higher than the those included in the latest IPF analysis.

Reference

Partanen JJ, Häppölä P, Zhou W, et al. Leveraging global multi-ancestry meta-analysis in the study of idiopathic pulmonary fibrosis genetics. Cell Genomics. 2022;2(10). doi:10.1016/j.xgen.2022.100181