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Enrichment of IGF-1R and PPARγ signalling pathways in orbital inflammatory diseases: steps toward understanding pathogenesis
  1. Rohan Verma1,2,
  2. Dongseok Choi2,3,4,5,
  3. Allison J Chen6,
  4. Christina A Harrington7,
  5. David J Wilson2,
  6. Hans E Grossniklaus8,
  7. Roger A Dailey1,2,
  8. John Ng1,2,
  9. Eric A Steele1,2,
  10. Stephen R Planck2,9,
  11. Bobby S Korn6,
  12. Don Kikkawa6,
  13. Craig N Czyz10,
  14. Jill A Foster11,
  15. Michael Kazim12,
  16. Gerald J Harris13,
  17. Deepak P Edward14,15,
  18. Haila Al-Hussain15,
  19. Azza M Y Maktabi15,
  20. Chris Alabiad16,
  21. Armando Garcia16,
  22. James T Rosenbaum2,5,9
  1. 1Oculofacial Plastic and Reconstructive Surgery, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA
  2. 2Casey Eye Institute, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA
  3. 3OHSU-PSU School of Public Health, Oregon Health & Science University, Portland, Oregon, USA
  4. 4Graduate School of Dentistry, Kyung Hee University, Seoul, South Korea
  5. 5Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
  6. 6Oculofacial Plastic and Reconstructive Surgery, University of California San Diego- Shiley Eye Institute and Viterbi Family Department of Ophthalmology, La Jolla, California, USA
  7. 7Integrated Genomics Laboratory, Oregon Health & Science University, Portland, Oregon, USA
  8. 8Emory Eye Center, Emory University, Atlanta, Georgia, USA
  9. 9Devers Eye Institute, Legacy Health System, Portland, Oregon, USA
  10. 10Oculofacial Plastic and Reconstructive Surgery, Ohio Health, Columbus, Ohio, USA
  11. 11Oculofacial Plastic and Reconstructive Surgery, The Ohio State University, Nationwide Children’s Hospital, Ophthalmic Surgeons and Consultants of Ohio, Columbus, Ohio, USA
  12. 12Edward S Harkness Eye Institute, Columbia University, New York, New York, USA
  13. 13Oculofacial Plastic and Reconstructive Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
  14. 14Ophthalmology and Visual Sciences, University of Illinois College of Medicine, Chicago, Illinois, USA
  15. 15Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia
  16. 16Oculofacial Plastic and Reconstructive Surgery, University of Miami Health System Bascom Palmer Eye Institute, Miami, Florida, USA
  1. Correspondence to Dr James T Rosenbaum, Ophthalmology, Oregon Health & Science University Casey Eye Institute, Portland, OR 97239, USA; rosenbaj{at}ohsu.edu

Abstract

Background Orbital inflammatory disease (OID) encompasses a wide range of pathology including thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis and non-specific orbital inflammation (NSOI), accounting for up to 6% of orbital diseases. Understanding the underlying pathophysiology of OID can improve diagnosis and help target therapy.

Aims To test the hypothesis that shared signalling pathways are activated in different forms of OID.

Methods In this secondary analysis, pathway analysis was performed on the previously reported differentially expressed genes from orbital adipose tissue using patients with OID and healthy controls who were characterised by microarray. For the original publications, tissue specimens were collected from oculoplastic surgeons at 10 international centres representing four countries (USA, Canada, Australia and Saudi Arabia). Diagnoses were independently confirmed by two masked ocular pathologists (DJW, HEG). Gene expression profiling analysis was performed at the Oregon Health & Science University. Eighty-three participants were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 25 with NSOI and 20 healthy controls.

Results Among the 83 subjects (mean (SD) age, 52.8 (18.3) years; 70% (n=58) female), those with OID demonstrated perturbation of the downstream gene expressions of the IGF-1R (MAPK/RAS/RAF/MEK/ERK and PI3K/Akt/mTOR pathways), peroxisome proliferator-activated receptor-γ (PPARγ), adipocytokine and AMPK signalling pathways compared with healthy controls. Specifically, GPA samples differed from controls in gene expression within the insulin-like growth factor-1 receptor (IGF-1R, PI3K-Akt (p=0.001), RAS (p=0.005)), PPARγ (p=0.002), adipocytokine (p=0.004) or AMPK (p=<0.001) pathways. TAO, sarcoidosis and NSOI samples were also found to have statistically significant differential gene expression in these pathways.

Conclusions Although OID includes a heterogenous group of pathologies, TAO, GPA, sarcoidosis and NSOI share enrichment of common gene signalling pathways, namely IGF-1R, PPARγ, adipocytokine and AMPK. Pathway analyses of gene expression suggest that other forms of orbital inflammation in addition to TAO may benefit from blockade of IGF-1R signalling pathways.

  • inflammation
  • orbit
  • experimental – laboratory

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Footnotes

  • Contributors RV, SRP, CAH and JTR helped in the study concept and design. Analysis and interpretation of data were done by RV, DC, AJC, SRP, CAH, DJW and JTR. Acquisition of data was done by RV, DJW, HEG, CAH, RAD, JN, EAS, SRP, BSK, DK, CNC, JAF, MK, GJH, DPE, HA-H, AMYM, CA, AG and JTR. Drafting of the manuscript was done by RV, DC, AJC and JTR.

  • Funding This research was supported by funding from National Institutes of Health (NIH) USA Grants EY020249 (JTR) and an NIH/NEI Core Grant P30 EY010572. JTR receives support from the Grandmaison Fund for Autoimmunity Research, the William and Mary Bauman Foundation, the Stan and Madelle Rosenfeld Family Trust and Research to Prevent Blindness (no award number from these sources). The sponsors did not have any role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the manuscript for publication.

  • Competing interests JTR has in the past consulted for Genentech/Roche and was a coinvestigator on a study funded by Genentech to evaluate the use of rituximab for orbital inflammatory diseases. JTR, RAD, BSK, DOK, and GJH are consultants to Horizon Pharmaceuticals which manufactures teprotumumab. JTR receives research support from Horizon Pharmaceuticals.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the IRB of Oregon Health & Science University, Study 00006301 and at each of the other contributing centres: Emory University IRB, University of California San Diego IRB, Mount Carmel (Ohio) IRB, Columbia University IRB, Medical College of Wisconsin IRB, King Khaled Eye Specialist Hospital Human Ethics Committee/Institutional Review Board, University of Miami IRB, Wake Forest University IRB, University of British Columbia Clinical Research Ethics Board, and Royal Adelaide Hospital Research Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. All the individual participant data that underlie the results reported in this article after deidentification will be shared and available upon request to investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose for individual participant data meta-analysis. Proposal should be directed to rosenbaj@ohsu.edu. To gain access, data requestors will need to sign a data access agreement.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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