Genome-Wide Expression Profiling of Complex Regional Pain Syndrome

Citation: Jin E-H, Zhang E, Ko Y, Sim WS, Moon DE, et al. ( Genome-Wide Expression Profiling of Complex Regional Pain Syndrome Eun-Heui Jin 0 Enji Zhang 0 Youngkwon Ko 0 Woo Seog Sim 0 Dong Eon Moon 0 Keon Jung Yoon 0 Jang Hee Hong 0 Won Hyung Lee 0 Michael Costigan, Boston Children's Hospital and Harvard Medical School, United States of America 0 1 Research Institute for Medical Sciences, College of Medicine, Chungnam National University , Daejeon , Korea , 2 Department of Anesthesia and Pain Medicine, Chungnam National University Hospital , Daejeon , Korea , 3 Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , Korea , 4 Department of Anaesthesiology and Pain Medicine, College of Medicine, The Catholic University , Seoul , Korea , 5 Department of Anaesthesiology and Pain Medicine, College of Medicine, The Catholic University , Daejeon , Korea , 6 Department of Phamacology, College of Medicine, Chungnam National University , Daejeon , Korea , 7 Clinical Trials Center, Chungnam National University Hospital , Daejeon , Korea Complex regional pain syndrome (CRPS) is a chronic, progressive, and devastating pain syndrome characterized by spontaneous pain, hyperalgesia, allodynia, altered skin temperature, and motor dysfunction. Although previous gene expression profiling studies have been conducted in animal pain models, there genome-wide expression profiling in the whole blood of CRPS patients has not been reported yet. Here, we successfully identified certain pain-related genes through genome-wide expression profiling in the blood from CRPS patients. We found that 80 genes were differentially expressed between 4 CRPS patients (2 CRPS I and 2 CRPS II) and 5 controls (cut-off value: 1.5-fold change and p,0.05). Most of those genes were associated with signal transduction, developmental processes, cell structure and motility, and immunity and defense. The expression levels of major histocompatibility complex class I A subtype (HLA-A29.1), matrix metalloproteinase 9 (MMP9), alanine aminopeptidase N (ANPEP), L-histidine decarboxylase (HDC), granulocyte colony-stimulating factor 3 receptor (G-CSF3R), and signal transducer and activator of transcription 3 (STAT3) genes selected from the microarray were confirmed in 24 CRPS patients and 18 controls by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). We focused on the MMP9 gene that, by qRT-PCR, showed a statistically significant difference in expression in CRPS patients compared to controls with the highest relative fold change (4.061.23 times and p = 1.461024). The up-regulation of MMP9 gene in the blood may be related to the pain progression in CRPS patients. Our findings, which offer a valuable contribution to the understanding of the differential gene expression in CRPS may help in the understanding of the pathophysiology of CRPS pain progression. - Funding: This study was supported by a grant from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A070001) and Chungnam National University Hospital Research Fund, 2013. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Complex regional pain syndrome (CRPS) is a chronic, progressive, and devastating pain syndrome that is characterized by spontaneous pain, hyperalgesia, allodynia, altered skin temperature, and motor dysfunction [1,2]. CRPS is generally classified into 2 types by the absence or presence of nerve injury. Patients with CRPS type I show no nerve injury, while type II patients exhibit nerve injury [3]. Due to the phenotypic complexity of CRPS, it is difficult to conduct a human based genome-wide association study in CRPS. Nonetheless, microarray tools have been commonly used to identify novel biomarkers that are known to contribute to pain pathways in animal pain models. Genome-wide expression analyses have been successfully performed only in animals. A different regulation of 86 genes after nerve injury was detected by a cDNA microarray analysis of spinal nerves from a rat model of neuropathic pain [4]. Furthermore, 124 co-regulated genes were identified in 3 neuropathic pain models (spared nerve injury, chronic construction injury, and spinal nerve ligation) by gene expression profiling of the rat dorsal root ganglion (DRG). Additionally, following a microarray-based screening study in large international pain cohort [5], a genetic association study was performed using single nucleotide polymorphisms (SNPs) of the potassium channel alpha subunit, KCNS1. In addition to animal studies, recent studies focused on the identification of novel molecules or genetic loci related to neuropathic pain in humans suffering from CPRS. A genetic association study conducted in CRPS patients and controls provided a new CRPS susceptibility locus (D6S1014) in human leukocyte antigen (HLA) class I region [6]. Uceyler et al. compared the cytokine expression (at the mRNA and protein level) in the serum between CRPS II or CRPS I patients and controls. The mRNA and protein levels of transforming growth factor (TGF)-b1 and interleukin (IL)-2 were higher and those of IL-4 and IL-10 were lower in CRPS patients than in controls [7]. 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