Aims and objectives. Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unknown aetiology and without any curative treatment. A recent meta-analysis suggested causal variants for IPF at three loci in the Finnish population, previously reported coding variants in TERT and SPDL1 and a newly identified missense variant in KIF15. This observational study was designed to determine whether these variants produce clinical phenotypes in a well-characterized Finnish IPF cohort. 

Methods. The study population consisted of 138 patients with IPF who were diagnosed and treated at Helsinki University Hospital and genotyped in the FinnGen FinnIPF study. More than 25 clinical parameters were collected by two pulmonologists who were blinded to the genetic data and analysed separately for patients with TERT loss-of-function and missense variants, SPDL1 missense, KIF15 missense, a MUC5B variant commonly present in patients with IPF, or no variants.

Results. The novel KIF15 missense variant had a major effect on morbidity, disease course, and mortality; these patients were markedly younger at the time of diagnosis, transplantation, or death and needed oxygen therapy more often than other patients. The variants for TERT and MUC5B had similar effects on the patient?s clinical course, as previously described. No distinct phenotypes were observed in patients with the SPDL1-variant.

Conclusions. We found that the KIF15 missense variant produces a distinct IPF phenotype associated with the early onset of the disease, leading to disease progression to transplantation or death at early age.