Evaluating whole-genome expression differences in idiopathic and diabetic adhesive capsulitis

Joshua A Gordon; Ali S Farooqi; Emilie Rabut; G Russell Huffman; Jonathan Schug; John D Kelly; George R Dodge

doi:10.1016/j.jse.2021.06.016

Evaluating whole-genome expression differences in idiopathic and diabetic adhesive capsulitis

J Shoulder Elbow Surg. 2022 Jan;31(1):e1-e13. doi: 10.1016/j.jse.2021.06.016. Epub 2021 Aug 2.

Authors

Joshua A Gordon¹, Ali S Farooqi¹, Emilie Rabut¹, G Russell Huffman¹, Jonathan Schug², John D Kelly¹, George R Dodge³

Affiliations

¹ Department of Orthopaedic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
² Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³ Department of Orthopaedic Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz Medical Center, United States Department of Veterans Affairs, Philadelphia, PA, USA. Electronic address: gdodge@upenn.edu.

Abstract

Background: Diabetic patients have a greater incidence of adhesive capsulitis (AC) and a more protracted disease course than patients with idiopathic AC. The purpose of this study was to compare gene expression differences between AC with diabetes mellitus and AC without diabetes mellitus.

Methods: Shoulder capsule samples were prospectively obtained from diabetic or nondiabetic patients who presented with shoulder dysfunction and underwent arthroscopy (N = 16). Shoulder samples of AC with and without diabetes (n = 8) were compared with normal shoulder samples with and without diabetes as the control group (n = 8). Shoulder capsule samples were subjected to whole-transcriptome RNA sequencing, and differential expression was analyzed with EdgeR. Only genes with a false discovery rate < 5% were included for further functional enrichment analysis.

Results: The sample population had a mean age of 47 years (range, 24-62 years), and the mean hemoglobin A_1c level for nondiabetic and diabetic patients was 5.18% and 8.71%, respectively. RNA-sequencing analysis revealed that 66 genes were differentially expressed between diabetic patients and nondiabetic patients with AC whereas only 3 genes were differentially expressed when control patients with and without diabetes were compared. Furthermore, 286 genes were differentially expressed in idiopathic AC patients, and 61 genes were differentially expressed in diabetic AC patients. On gene clustering analysis, idiopathic AC was enriched with multiple structural and muscle-related pathways, such as muscle filament sliding, whereas diabetic AC included a greater number of hormonal and inflammatory signaling pathways, such as cellular response to corticotropin-releasing factor.

Conclusions: Whole-transcriptome expression profiles demonstrate a fundamentally different underlying pathophysiology when comparing diabetic AC with idiopathic AC, suggesting that these conditions are distinct clinical entities. The new genes expressed explain the differences in the disease course and suggest new therapeutic targets that may lead to different treatment paradigms in these 2 subsets.

Keywords: Frozen shoulder; RNA sequencing; adhesive capsulitis; corticosteriods; diabetes; inflammation; whole genome sequencing.

MeSH terms

Arthroscopy
Bursitis* / genetics
Diabetes Mellitus* / genetics
Humans
Middle Aged
Shoulder
Shoulder Joint*

Abstract

MeSH terms

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