Polygenic risk scores for rheumatoid arthritis and idiopathic pulmonary fibrosis and associations with RA, interstitial lung abnormalities, and quantitative interstitial abnormalities among smokers

Gregory C McDermott¹, Matthew Moll², Michael H Cho³, Keigo Hayashi⁴, Pierre-Antoine Juge⁵, Tracy J Doyle⁶, Misti L Paudel¹, Gregory L Kinney⁷, Vanessa L Kronzer⁸, John S Kim⁹, Lauren A O'Keeffe⁴, Natalie A Davis⁴, Elana J Bernstein¹⁰, Paul F Dellaripa¹, Elizabeth A Regan¹¹, Gary M Hunninghake⁶, Edwin K Silverman³, Samuel Y Ash¹², Raul San Jose Estepar⁶, George R Washko⁶, Jeffrey A Sparks¹³

Affiliations

¹ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
² Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Pulmonary, Allergy, Sleep and Critical Care Medicine Section, Department of Medicine, VA Boston Healthcare System, West Roxbury, MA, USA.
³ Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA; Université de Paris Cité, INSERM UMR 1152, F-75018 Paris, France; Service de Rhumatologie, Hôpital Bichat-Claude Bernard, AP-HP, F-75018 Paris, France.
⁶ Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Colorado School of Public Health, Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁸ Division of Rheumatology, Mayo Clinic, Rochester, MN, USA.
⁹ Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA.
¹⁰ Division of Rheumatology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
¹¹ Division of Rheumatology, National Jewish Health, Denver, CO, USA.
¹² Division of Pulmonary and Critical Care Medicine, South Shore Health, South Weymouth, MA, USA.
¹³ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: jsparks@bwh.harvard.edu.

PMID: 40090204
PMCID: PMC12048222 (available on 2026-06-01)
DOI: 10.1016/j.semarthrit.2025.152708

Multicenter Study

Polygenic risk scores for rheumatoid arthritis and idiopathic pulmonary fibrosis and associations with RA, interstitial lung abnormalities, and quantitative interstitial abnormalities among smokers

Gregory C McDermott et al. Semin Arthritis Rheum. 2025 Jun.

. 2025 Jun:72:152708.

doi: 10.1016/j.semarthrit.2025.152708. Epub 2025 Mar 15.

Authors

Affiliations

¹ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
² Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Pulmonary, Allergy, Sleep and Critical Care Medicine Section, Department of Medicine, VA Boston Healthcare System, West Roxbury, MA, USA.
³ Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA; Université de Paris Cité, INSERM UMR 1152, F-75018 Paris, France; Service de Rhumatologie, Hôpital Bichat-Claude Bernard, AP-HP, F-75018 Paris, France.
⁶ Harvard Medical School, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁷ Colorado School of Public Health, Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁸ Division of Rheumatology, Mayo Clinic, Rochester, MN, USA.
⁹ Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA.
¹⁰ Division of Rheumatology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
¹¹ Division of Rheumatology, National Jewish Health, Denver, CO, USA.
¹² Division of Pulmonary and Critical Care Medicine, South Shore Health, South Weymouth, MA, USA.
¹³ Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: jsparks@bwh.harvard.edu.

PMID: 40090204
PMCID: PMC12048222 (available on 2026-06-01)
DOI: 10.1016/j.semarthrit.2025.152708

Abstract

Objective: Genome-wide association studies (GWAS) facilitate construction of polygenic risk scores (PRSs) for rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF). We investigated associations of RA and IPF PRSs with RA and high-resolution chest computed tomography (HRCT) parenchymal lung abnormalities.

Methods: Participants in COPDGene, a prospective multicenter cohort of current/former smokers, had chest HRCT at study enrollment. Using genome-wide genotyping, RA and IPF PRSs were constructed using GWAS summary statistics. HRCT imaging underwent visual inspection for interstitial lung abnormalities (ILA) and quantitative CT (QCT) analysis using a machine-learning algorithm that quantified percentage of normal lung, interstitial abnormalities, and emphysema. RA was identified through self-report and DMARD use. We investigated associations of RA and IPF PRSs with RA, ILA, and QCT features using multivariable logistic and linear regression.

Results: We analyzed 9,230 COPDGene participants (mean age 59.6 years, 46.4 % female, 67.2 % non-Hispanic White, 32.8 % Black/African American). In non-Hispanic White participants, RA PRS was associated with RA diagnosis (OR 1.32 per unit, 95 %CI 1.18-1.49) but not ILA or QCT features. Among non-Hispanic White participants, IPF PRS was associated with ILA (OR 1.88 per unit, 95 %CI 1.52-2.32) and quantitative interstitial abnormalities (adjusted β=+0.50 % per unit, p = 7.3 × 10^-8) but not RA. There were no statistically significant associations among Black/African American participants.

Conclusions: RA and IPF PRSs were associated with their intended phenotypes among non-Hispanic White participants but performed poorly among Black/African American participants. PRS may have future application to risk stratify for RA diagnosis among patients with ILD or for ILD among patients with RA.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pierre-Antoine Juge reports a relationship with Bristol Myers Squibb Co that includes: funding grants. Pierre-Antoine Juge reports a relationship with Boehringer Ingelheim GmbH that includes: funding grants. Pierre-Antoine Juge reports a relationship with AstraZeneca Pharmaceuticals LP that includes: funding grants. Pierre-Antoine Juge reports a relationship with Novartis AG that includes: funding grants. Matthew Moll reports a relationship with Bayer AG that includes: funding grants. Michael H Cho reports a relationship with Bayer AG that includes: funding grants. Michael H Cho reports a relationship with Apogee Therapeutics Inc that includes: consulting or advisory. Tracy J Doyle reports a relationship with Sanofi SA that includes: employment. Tracy J Doyle reports a relationship with Bayer AG that includes: funding grants. Tracy J Doyle reports a relationship with Bristol Myers Squibb Co that includes: funding grants. Tracy J Doyle reports a relationship with Boehringer Ingelheim GmbH that includes: consulting or advisory. Tracy J Doyle reports a relationship with LEK Consulting that includes: consulting or advisory. Tracy J Doyle reports a relationship with Genentech Inc that includes: funding grants. Misti L Paudel reports a relationship with UnitedHealth Group Inc that includes: equity or stocks. Paul F Dellaripa reports a relationship with Genentech Inc that includes: funding grants. Paul F Dellaripa reports a relationship with Bristol Myers Squibb Co that includes: funding grants. Paul F Dellaripa reports a relationship with UptoDate Inc that includes: funding grants. Gary M Hunninghake reports a relationship with Boehringer Ingelheim GmbH that includes: consulting or advisory. Gary M Hunninghake reports a relationship with Gerson Lehrman Group Inc that includes: consulting or advisory. Gary M Hunninghake reports a relationship with Chugai Pharmaceutical Co Ltd that includes: consulting or advisory. Edwin K Silverman reports a relationship with Bayer AG that includes: funding grants. Edwin K Silverman reports a relationship with Northpond Laboratories that includes: funding grants. Raul San Jose Estepar reports a relationship with Boehringer Ingelheim GmbH that includes: funding grants. Raul San Jose Estepar reports a relationship with Quantitative Imaging Solutions that includes: employment and equity or stocks. George R Washko reports a relationship with Boehringer Ingelheim GmbH that includes: funding grants. George R Washko reports a relationship with Pulmonx Corp that includes: consulting or advisory. George R Washko reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. George R Washko reports a relationship with Novartis AG that includes: consulting or advisory. George R Washko reports a relationship with Novartis that includes: consulting or advisory. George R Washko reports a relationship with Vertex Pharmaceuticals Incorporated that includes: consulting or advisory. George R Washko reports a relationship with Quantitative Imaging Solutions that includes: employment and equity or stocks. Jeffrey A Sparks reports a relationship with Bristol Myers Squibb Co that includes: funding grants. Jeffrey A Sparks reports a relationship with Sonoma Biotherapeutics Inc that includes: funding grants. Jeffrey A Sparks reports a relationship with AbbVie Inc that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with Amgen Inc that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with Boehringer Ingelheim GmbH that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with Gilead Sciences Inc that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with INOVA Diagnostics Inc that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with Johnson and Johnson that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with Merck & Co Inc that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with MustangBio that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with Optum that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with Pfizer Inc that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with Sana Biotechnology Inc that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with Sobi Inc that includes: consulting or advisory. Jeffrey A Sparks reports a relationship with ReCor that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

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Polygenic risk scores for rheumatoid arthritis and idiopathic pulmonary fibrosis and associations with RA, interstitial lung abnormalities, and quantitative interstitial abnormalities among smokers

Affiliations

Polygenic risk scores for rheumatoid arthritis and idiopathic pulmonary fibrosis and associations with RA, interstitial lung abnormalities, and quantitative interstitial abnormalities among smokers

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials