RT Journal Article
SR Electronic
T1 Enrichment of IGF-1R and PPARγ signalling pathways in orbital inflammatory diseases: steps toward understanding pathogenesis
JF British Journal of Ophthalmology
JO Br J Ophthalmol
FD BMJ Publishing Group Ltd.
SP 1012
OP 1017
DO 10.1136/bjophthalmol-2020-318330
VO 106
IS 7
A1 Rohan Verma
A1 Dongseok Choi
A1 Allison J Chen
A1 Christina A Harrington
A1 David J Wilson
A1 Hans E Grossniklaus
A1 Roger A Dailey
A1 John Ng
A1 Eric A Steele
A1 Stephen R Planck
A1 Bobby S Korn
A1 Don Kikkawa
A1 Craig N Czyz
A1 Jill A Foster
A1 Michael Kazim
A1 Gerald J Harris
A1 Deepak P Edward
A1 Haila Al-Hussain
A1 Azza M Y Maktabi
A1 Chris Alabiad
A1 Armando Garcia
A1 James T Rosenbaum
YR 2022
UL http://bjo.bmj.com/content/106/7/1012.abstract
AB 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.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.