Rare variants and survival of patients with idiopathic pulmonary fibrosis

Aitana Alonso-González; David Jáspez; Jose Miguel Lorenzo-Salazar; Shwu‐Fan Ma; Emma Strickland; Josyf C. Mychaleckyj; John S. Kim; Yong Huang; Ayodeji Adegunsoye; Justin M. Oldham; Iain Steward; Philip L. Molyneaux; Toby M. Maher; Louise V. Wain; Richard J. Allen; Gisli R. Jenkins; Jonathan A. Kropski; Brian L. Yaspan; Timothy S. Blackwell; David Zhang; Christine Kim Garcia; Fernando J. Martínez; Imre Noth; Carlos Flores

doi:10.1101/2024.10.12.24315151

Genetic & Genomic MedicinemedRxivOct 12, 2024

Preprint

Rare variants and survival of patients with idiopathic pulmonary fibrosis

Aitana Alonso-González iD, David Jáspez iD, Jose Miguel Lorenzo-Salazar iD, Shwu‐Fan Ma iD, Emma Strickland iD, Josyf C. Mychaleckyj iD, John S. Kim iD, Yong Huang iD, Ayodeji Adegunsoye iD, Justin M. Oldham iD, Iain Steward, Philip L. Molyneaux iD, Toby M. Maher iD, Louise V. Wain iD, Richard J. Allen iD, Gisli R. Jenkins iD, Jonathan A. Kropski iD, Brian L. Yaspan iD, Timothy S. Blackwell iD, David Zhang iD, Christine Kim Garcia iD, Fernando J. Martínez iD, Imre Noth iD, Carlos Flores iD

Abstract

BackgroundThe clinical course of idiopathic pulmonary fibrosis (IPF) is highly variable and unpredictable, with multiple genetic variants influencing IPF outcomes. Notably, rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in these patients. Here we assessed whether rare qualifying variants (QVs) in monogenic adult-onset pulmonary fibrosis (PF) genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in individuals carrying these QVs. MethodsWe identified QVs in telomere and non-telomere genes linked to monogenic PF forms using whole-genome sequences (WGS) from 888 Pulmonary Fibrosis Foundation Patient Registry (PFFPR) individuals. We also derived a PRS for IPF (PRS-IPF) from 19 previously published common sentinel IPF variants. Using regression models, we then examined the mutual relationships of QVs and PRS-IPF and their association with survival. Validation of results was sought in WGS from an independent IPF study (PROFILE, n=472), and results from the two cohorts were meta-analyzed. ResultsCarriers of QVs in monogenic adult-onset PF genes, representing nearly 1 out of 6 IPF patients, were associated with lower PRS-IPF (Odds Ratio [OR]: 1.79; 95% Confidence Interval [CI]: 1.15-2.81; p=0.010) and shorter survival (Hazard Ratio [HR]: 1.53; 95% CI: 1.12-2.10; p=7.3x10-3). Notably, carriers of pathogenic variants at telomere genes showed the strongest association with survival (HR: 1.76; 95% CI: 1.13-2.76; p=0.013). The meta-analysis of the results showed a consistent direction of effect across both cohorts. ConclusionsWe revealed the opposite effects of QVs and PRS-IPF on IPF survival. Thus, a distinct IPF molecular subtype might be defined by QVs in monogenic adult-onset PF genes. Assessing the carrier status for QVs and modelling PRS-IPF promises to further contribute to predicting disease progression among IPF patients.

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