A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities

Matthew Moll, Anna L. Peljto, John S. Kim, Hanfei Xu, Catherine L. Debban, Xianfeng Chen, Aravind Menon, Rachel K. Putman, Auyon J. Ghosh, Aabida Saferali, Mizuki Nishino, Hiroto Hatabu, Brian D. Hobbs, Julian Hecker, Gregory McDermott, Jeffrey A. Sparks, Louise V. Wain, Richard J. Allen, Martin D. Tobin, Benjamin A. RabySung Chun, Edwin K. Silverman, Ana C. Zamora, Victor E. Ortega, Christine K. Garcia, R. Graham Barr, Eugene R. Bleecker, Deborah A. Meyers, Robert J. Kaner, Stephen S. Rich, Ani Manichaikul, Jerome I. Rotter, Josée Dupuis, George T. O’Connor, Tasha E. Fingerlin, Gary M. Hunninghake, David A. Schwartz, Michael H. Cho

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case–control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 3 10295) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 3 10287) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ~sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NOM5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

Original languageEnglish (US)
Pages (from-to)791-801
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Volume208
Issue number7
DOIs
StatePublished - Oct 1 2023

Keywords

  • MUC5B
  • idiopathic pulmonary fibrosis
  • interstitial lung abnormalities
  • polygenic risk score

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Fingerprint

Dive into the research topics of 'A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities'. Together they form a unique fingerprint.

Cite this