Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF.
To identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data. For instruments we used genetic determinants of circulating proteins which reside cis to the encoded gene (cis-SNPs), identified by two genome-wide association studies (GWASs) in European individuals (3301 and 3200 subjects). We then applied MR methods to test if the levels of these circulating proteins influenced IPF susceptibility in the largest IPF GWAS (2668 cases and 8591 controls). We validated the MR results using colocalization analyses to ensure that both the circulating proteins and IPF shared a common genetic signal.
MR analyses of 834 proteins found that a one sd increase in circulating FUT3 and FUT5 was associated with a reduced risk of IPF (OR: 0.81, 95%CI: 0.74–0.88, p=6.3×10−7, and OR: 0.76, 95%CI: 0.68–0.86, p=1.1×10−5). Sensitivity analyses including multiple-cis SNPs provided similar estimates both for FUT3 (inverse variance weighted [IVW] OR: 0.84, 95%CI: 0.78–0.91, p=9.8×10−6, MR-Egger OR: 0.69, 95%CI: 0.50–0.97, p=0.03) and FUT5 (IVW OR: 0.84, 95%CI: 0.77–0.92, p=1.4×10−4, MR-Egger OR: 0.59, 95%CI: 0.38–0.90, p=0.01) FUT3 and FUT5 signals colocalized with IPF signals, with posterior probabilities of a shared genetic signal of 99.9% and 97.7%. Further transcriptomic investigations supported the protective effects of FUT3 for IPF.
An efficient MR scan of 834 circulating proteins provided evidence that genetically increased circulating FUT3 level is associated with reduced risk of IPF.
Footnotes
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Conflict of interest: Dr. Nakanishi has nothing to disclose.
Conflict of interest: Dr. Cerani has nothing to disclose.
Conflict of interest: Dr. Forgetta has nothing to disclose.
Conflict of interest: Dr. Zhou has nothing to disclose.
Conflict of interest: Dr. Allen has nothing to disclose.
Conflict of interest: Dr. Leavy has nothing to disclose.
Conflict of interest: Dr. Koido has nothing to disclose.
Conflict of interest: Dr. Assayag reports grants and personal fees from Boehringer-Ingelheim Canada, personal fees from Hoffman-LaRoche Canada, personal fees from Astra-Zeneca Canada, outside the submitted work; .
Conflict of interest: Dr. Jenkins reports grants from Astra Zeneca, grants from Biogen, personal fees from Boehringer Ingelheim, personal fees from Daewoong, personal fees from Galapagos, grants from Galecto, grants from GlaxoSmithKline, personal fees from Heptares, non-financial support from NuMedii, grants and personal fees from Pliant, personal fees from Promedior, non-financial support from Redx, personal fees from Roche, other from Action for Pulmonary Fibrosis, outside the submitted work; .
Conflict of interest: Dr. Wain reports grants from GSK, outside the submitted work; .
Conflict of interest: Dr. Yang reports grants from NIH and personal fees from Eleven P15 related to research in pulmonary fibrosis, outside the submitted work. In addition, Dr. Yang has a patent Circulating Biomarkers of Preclinical Pulmonary Fibrosis pending.
Conflict of interest: Dr. Lathorp has nothing to disclose.
Conflict of interest: Dr. Wolters reports grants and personal fees from Boehringer Ingelheim, personal fees from Gossamer Bio, grants and personal fees from Roche/Genentech, personal fees from Blade Therapeutics, personal fees from Pliant, outside the submitted work; .
Conflict of interest: Dr. Schwartz reports grants from NIH-NHLBI, grants from NIH-NHLBI, grants from NIH-NHLBI, grants from NIH-NHLBI, grants from DOD Focused Program Grant, during the conduct of the study; personal fees from Eleven P15, Inc., outside the submitted work; In addition, Dr. Schwartz has a patent Compositions and Methods of Treating or Preventing Fibrotic Diseases pending, a patent Biomarkers for the diagnosis and treatment of fibrotic lung disease pending, and a patent Methods and Compositions for Risk Prediction, Diagnosis, Prognosis, and Treatment of Pulmonary Disorders issued.
Conflict of interest: Dr. Richards has served as an advisor to GlaxoSmithKline and Deerfield Capital.
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- Received October 27, 2020.
- Accepted June 14, 2021.
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