Citations 2
Association of a Polygenic Risk Score with Diagnosis and Outcomes in Idiopathic Pulmonary Fibrosis
Kalra, S. , Grilli, Christopher, Coombes, Brandon J. , Armasu, Sebastian M. , Upjohn, D, Egan, Jan B. , Chen, Qingwen , Tern, Courtney , Zhang, Chengyue, Rose, Jonathan A. , Putman, Rachel, McDermott, Greg, Hsieh, Yuli Lily , Bublitz, Michele L., Carmona, Eva M. , Klee, Eric W, Lazaridis, K, Peljto, Anna L. , Schwartz, D A, Silverman, Edwin K. , Olson, Janet, Walker, T, Zamora, Ana C., Zein, Joe , Ortega, V E, Cohort, Tapestry, McDermott, Gregory C , Kalra, Sean S , Grilli, Christopher B , Armasu, Sebastian , Upjohn, David P , Hsieh, Yuli L , Lasky-Su, Jessica , Silverman, Edwin K , Allen, Richard J , Walker, T'Nita, Wain, Louise V , Zamora, Ana, Zein, Joe G, Hunninghake, Gary M , Moll, Matthew , Cho, Michael H , Carmona, Eva M , McDermott, Gregory , Coombes, Brandon J , Putman, Rachel K. , Kn, Lazaridis, Lasky‐Su, Jessica , Dudbridge, Frank , Allen, Richard J. , Olson, JA, Hunninghake, Gary M. , Ali, Ahmad Hafiz , Sekulić, Aleksandar , Athreya, Arjun P. , Clermont, Blake J, N, Brittany, Burnap, Graddy, Courtney B., Cahn, Elliot, Klee, Eric W. , Sicotte, Hugues , Ekpoh, Idara U., Frank, Jacob A., Bruflat, Jamie K., Kemppainen, Jennifer L., Samadder, Jewel, Presutti, John J, Leitzke, Jon W, Lazaridis, Konstantinos N. , Tree, Kristine M, Jones, Leila A, Bandel, Lorelei A. , Karow, Mary E., Peterson, Melanie M., Bublitz, Michelle L. , Morales-Rosado, Joel, Erwin, Nate P., Larson, Nicholas B. , Olson, Rory, Vierkant, Robert A., Pignolo, Robert J. , Safgren, Stephanie, Bagaria, Sanjay P. , Tian, Shulan , Kaggal, Suneetha, Walker, T'Nita S., Wilson, Tammy A., McAllister, Tammy M., Tan-Arroyo, Jennifer, Luehrs, Tony, Ortega, Victor E. , Chen, Wenan , Cho, Michael H.
American Journal of Respiratory and Critical Care Medicine | July 2, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic progressive pulmonary fibrosis and high mortality. Genetic markers, summarized into a polygenic risk score (PRS), associate with IPF in well-phenotyped research cohorts. Objectives To evaluate the performance of the PRS using real-world data from routinely captured electronic healthcare records. Methods We conducted an observational study evaluating the association of a PRS for IPF with electronic healthcare record diagnosis of IPF as well as lung transplant-free survival in four independent cohorts; the Mass General Brigham Biobank (MGBB), Mayo Clinic Biobank (MCBB), Mayo Clinic Tapestry Cohort (Tapestry), and U.K. Biobank (UKBB). We used multivariable logistic regression and multivariable Cox proportional hazards models adjusting for age, gender, and principal components of ancestry. The cohorts then underwent fixed and random effects meta-analysis. Measurements and Main Results Of 37,709; 44,195; 43,202; and 447,422 participants from MGBB, MCBB, Tapestry and UKBB respectively, 1,015 (2.7%) 2,879 (6.5%), 1,310 (3.0%), and 2,742 (0.6%) participants had an IPF diagnosis. Meta-analysis demonstrated a high-risk PRS associated with IPF diagnosis, OR 2.88 (95%CI 2.41-3.44) compared to all other individuals. A high-risk PRS also associated with the composite endpoint of mortality or lung transplant among those with an IPF diagnosis, HR 1.23(95%CI 1.11-1.35) compared to all other individuals. Conclusions A PRS can identify those at risk for an IPF diagnosis and mortality in biobank-scale data, which may have implications for clinical decisions. Further work is necessary to evaluate the utility of adding genetics in clinical settings.
A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities
Peljto, Anna L. , Xu, Hanfei , Debban, Catherine L., Chen, Xianfeng , Menon, Aravind , Putman, Rachel K. , Saferali, Aabida , Nishino, Mizuki , Hatabu, Hiroto , Hobbs, Brian D. , McDermott, Gregory C , Sparks, Jeffrey A. , Allen, Richard J. , Raby, Benjamin A. , Chun, Sung , Silverman, Edwin K. , Zamora, Ana, Ortega, Victor E. , Bleecker, Eugene R. , Meyers, Deborah A. , Rotter, Jerome I. , Fingerlin, Tasha E. , Hunninghake, Gary M. , Peljto, Anna L , Menon, Aravind , Zamora, Ana C., Garcia, Christine K , Sparks, Jeffrey A , McDermott, Gregory , Rotter, Jerome I , Hobbs, Brian D , Allen, Richard J , Hunninghake, Gary M , Moll, Matthew , Kim, John S. , Ghosh, Auyon , Hecker, Julian , Wain, Louise V , Tobin, Martin D. , Barr, R. Graham , Kaner, Robert J. , Rich, Stephen S. , Manichaikul, Ani , Dupuis, Josée , O’Connor, George T. , Schwartz, David A. , Cho, Michael H.
American Journal of Respiratory and Critical Care Medicine | July 31, 2023 | Volume: 208 | Issue: 7 | Pages: 791-801
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 × 10−95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10−87) 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-NO-M5B 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.