Bioinformatics Analysis of Differentially Expressed Genes in Carpal Tunnel Syndrome Using RNA Sequencing
Abstract
Background: Carpal tunnel syndrome (CTS) is a common disease resulting from the median nerve entrapment at the wrist. Although CTS (prevalence=5%–10% in the general population) is the most common neuropathy, its molecular mechanisms need elucidation. We used bioinformatics to detect genes with differential expressions in CTS and introduce the molecular regulatory noncoding RNAs and signaling pathways involved.
Methods: The raw files of the RNA sequencing of CTS patients and controls were obtained from GEO (accession: GSE108023), and the samples were analyzed. Differentially expressed genes were isolated using DESeq2 R. Functional analyses were conducted on the signaling pathways, biological processes, molecular functions, and cellular components of the differentially expressed genes. Additionally, interactions between the most differentially expressed genes and miRNAs and lncRNAs were investigated bioinformatically.
Results: Upregulation and downregulation were observed in 790 and 922 genes, respectively. The signaling pathway analysis identified the metabolism pathways of arachidonic acid, linoleic acid, and tyrosine as the most significant pathways in CTS. Moreover, PLA2G2D and PLA2G2A with upregulated expressions and PLA2G2F, PLA2G4F, PLA2G4D, PLA2G3, and PLA2G4E with downregulated expressions were genes from the phospholipase family playing significant roles in the pathways. Further analyses demonstrated that hsa-miR-3150b-3p targeted PLA2G2A and PLA2G4F, and RP11-573D15.8-018 lncRNA had regulatory interactions with the aforementioned genes.
Conclusion: Molecular studies on CTS will clarify the involved signaling pathways and provide critical data for biomedical research, drug development, and clinical applications.
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3. Nagar KG (2014). A short review on carpel tunnel syndrome. J Med Pharm Allied Sci, 3(05):20-6.
4. Ibrahim I, Khan W, Goddard N, Smitham P (2012). Carpal tunnel syndrome: a review of the recent literature. Open Orthop J, 6:69-76.
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6. Bickel KD (2010). Educational Objectives. J Hand Surg Am, 35(1):147-52.
7. Burton C, Chesterton LS, Davenport G (2014). Diagnosing and managing carpal tunnel syndrome in primary care. Br J Gen Pract, 64(622):262-3.
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9. Moosazadeh M, Asadi-Aliabadi M, Rostami F, et al (2018). Prevalence of carpal tunnel syndrome in Iran: A systematic review and meta-analysis. J Mazandaran Univ Med Sci, 28(161):144-153.
10. Lozano-Calderón S, Anthony S, Ring D (2008). The quality and strength of evidence for etiology: example of carpal tunnel syndrome. J Hand Surg Am, 33(4):525-38.
11. Shiri R (2014). Hypothyroidism and carpal tunnel syndrome: A meta‐analysis. Muscle Nerve, 50(6):879-83.
12. Wiberg A, Ng M, Schmid AB, et al (2019). A genome-wide association analysis identifies 16 novel susceptibility loci for carpal tunnel syndrome. Nat Commun, 10(1):1030.
13. Werner RA, Andary M (2002). Carpal tunnel syndrome: pathophysiology and clinical neurophysiology. Clin Neurophysiol, 113(9):1373-81.
14. Camara-Lemarroy CR, Gonzalez-Moreno EI, Guzman-de la Garza FJ, et al (2012). Arachidonic acid derivatives and their role in peripheral nerve degeneration and regeneration. ScientificWorldJournal, 2012: 168953
15. Phillis JW, Horrocks LA, Farooqui AA (2006). Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Res Rev, 52(2):201-43.
16. Williams C (1971). Aspects of tyrosine metabolism in schizophrenia. Psychol Med, 1(4):286-91.
17. Norwood S, Liao J, Hammock BD, Yang G-Y (2010). Epoxyeicosatrienoic acids and soluble epoxide hydrolase: potential therapeutic targets for inflammation and its induced carcinogenesis. Am J Transl Res, 2(4):447-57.
18. Bryda J, Watroba S (2018). The proinflammatory role of lipoxygenases in rheumatoid arthritis. J Pre Clin Clin Res, 12(4):129-134.
19. Horrobin DF (1993). Fatty acid metabolism in health and disease: the role of Δ-6-desaturase. Am J Clin Nutr, 57(5 Suppl):732S-736S;
20. Van Doormaal J, Idema I, Muskiet F, et al (1988). Effects of short-term high dose intake of evening primrose oil on plasma and cellular fatty acid compositions, α-tocopherol levels, and erythropoiesis in normal and type 1 (insulin-dependent) diabetic men. Diabetologia, 31(8):576-84.
21. Tilvis R, Helve E, Miettinen T (1986). Improvement of diabetic control by continuous subcutaneous insulin infusion therapy changes fatty acid composition of serum lipids and erythrocytes in type 1 (insulin-dependent) diabetes. Diabetologia, 29(10):690-4.
22. Magy N, Liepnieks JJ, Gil H, Kantelip B, et al (2003). A transthyretin mutation (Tyr78Phe) associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis. Amyloid, 10(1):29-33.
23. Austin PJ, Moalem-Taylor G (2010). The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol, 229(1-2):26-50.
24. Lees JG, Fivelman B, Duffy SS, et al (2015). Cytokines in neuropathic pain and associated depression. Mod Trends Pharmacopsychiatry, 30:51-66.
25. Moalem-Taylor G, Baharuddin B, Bennett B, et al (2017). Immune dysregulation in patients with carpal tunnel syndrome. Sci Rep, 7(1):8218.
26. Schmid AB, Nee RJ, Coppieters MW (2013). Reappraising entrapment neuropathies–mechanisms, diagnosis and management. Man Ther, 18(6):449-57.
27. Grosser T, Ricciotti E, FitzGerald GA (2017). The cardiovascular pharmacology of nonsteroidal anti-inflammatory drugs. Trends Pharmacol Sci, 38(8):733-48.
28. Sala A, Proschak E, Steinhilber D, Rovati GE (2018). Two-pronged approach to anti-inflammatory therapy through the modulation of the arachidonic acid cascade. Biochem Pharmacol, 158:161-73.
29. Cheng L, Cao W, Behar J, et al (2005). Inflammation induced changes in arachidonic acid metabolism in cat LES circular muscle. Am J Physiol Gastrointest Liver Physiol, 288(4):G787-97.
30. Calabrese C, Triggiani M, Marone G, Mazzarella G (2000). Arachidonic acid metabolism in inflammatory cells of patients with bronchial asthma. Allergy, 55 Suppl 61:27-30.
31. Bassaganya-Riera J, Hontecillas R, Zimmerman DR, Wannemuehler MJ (2001). Dietary conjugated linoleic acid modulates phenotype and effector functions of porcine CD8+ lymphocytes. J Nutr, 131(9):2370-7.
32. Hayek MG, Han SN, Wu D, et al (1999). Dietary conjugated linoleic acid influences the immune response of young and old C57BL/6NCrlBR mice. J Nutr, 129(1):32-8.
33. Yang M, Pariza MW, Cook ME (2000). Dietary conjugated linoleic acid protects against end stage disease of systemic lupus erythematosus in the NZB/W F1 mouse. Immunopharmacol Immunotoxicol, 22(3):433-49.
34. Cook M, Miller C, Park Y, Pariza M (1993). Immune modulation by altered nutrient metabolism: nutritional control of immune-induced growth depression. Poult Sci, 72(7):1301-5.
35. Hontecillas R, Wannemeulher MJ, Zimmerman DR, et al (2002). Nutritional regulation of porcine bacterial-induced colitis by conjugated linoleic acid. J Nutr, 132(7):2019-27.
36. Li Y, Watkins BA (1998). Conjugated linoleic acids alter bone fatty acid composition and reduce ex vivo prostaglandin E 2 biosynthesis in rats fed n-6 or n-3 fatty acids. Lipids, 33(4):417-25.
37. Erdinest N, Shmueli O, Grossman Y, et al (2012). Anti-inflammatory effects of alpha linolenic acid on human corneal epithelial cells. Invest Ophthalmol Vis Sci, 53(8):4396-406.
38. Reilly MP, Lawson JA, FitzGerald GA (1998). Eicosanoids and isoeicosanoids: indices of cellular function and oxidant stress. J Nutr, 128(2 Suppl):434S-438S.
39. Nevalainen T, Aho H, Peuravuori H (1994). Secretion of group 2 phospholipase A2 by lacrimal glands. Invest Ophthalmol Vis Sci, 35(2):417-21.
40. Nevalainen T, Meri KM, Niemi M (1993). Synovial‐type (group II) phospholipase A2 human seminal plasma. Andrologia, 25(6):355-8.
41. Touqui L, Alaoui-El-Azher M (2001). Mammalian secreted phospholipases a2 and their pathophysiolo-gical significance in inflammatory diseases. Curr Mol Med, 1(6):739-54.
42. Kugiyama K, Ota Y, Sugiyama S, et al (2000). Prognostic value of plasma levels of secretory type II phospholipase A2 in patients with unstable angina pectoris. Am J Cardiol, 86(7):718-22.
43. Miki Y, Yamamoto K, Taketomi Y, et al (2013). Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators. J Exp Med, 210(6):1217-34.
44. Hoeft B, Linseisen J, Beckmann L, et al (2010). Polymorphisms in fatty acid metabolism-related genes are associated with colorectal cancer risk. Carcinogenesis, 31(3):466-72.
45. Ray U, Roy D, Jin L, et al (2021). Group III phospholipase A2 downregulation attenuated survival and metastasis in ovarian cancer and promotes chemo-sensitization. J Exp Clin Cancer Res, 40(1):182.
46. Shao S, Chen J, Swindell WR, et al (2021). Phospholipase A2 enzymes represent a shared pathogenic pathway in psoriasis and pityriasis rubra pilaris. JCI Insight, 6(20): e151911.
47. Dykes IM, Emanueli C (2017). Transcriptional and post-transcriptional gene regulation by long non-coding RNA. Genomics Proteomics Bioinformatics, 15(3):177-186.
48. Malakootian M, Gholipour A, Bagheri Moghaddam M, et al (2022). Potential roles of circular rnas and environmental and clinical factors in intervertebral disc degeneration. Environ Health Eng Manag, 9(2):189-200.
49. Taheri Bajgan E, Gholipour A, Faghihi M, et al (2022). Linc-ROR has a Potential ceRNA Activity for OCT4A by Sequestering miR-335-5p in the HEK293T Cell Line. Biochem Genet, 60:1007–1024.
2. Malakootian M, Soveizi M, Gholipour A, Oveisee M (2023). Pathophysiology, diagnosis, treatment, and genetics of carpal tunnel syndrome: a review. Cell Mol Neurobiol, 43(5):1817-31.
3. Nagar KG (2014). A short review on carpel tunnel syndrome. J Med Pharm Allied Sci, 3(05):20-6.
4. Ibrahim I, Khan W, Goddard N, Smitham P (2012). Carpal tunnel syndrome: a review of the recent literature. Open Orthop J, 6:69-76.
5. Padua L, Coraci D, Erra C, et al (2016). Carpal tunnel syndrome: clinical features, diagnosis, and management. Lancet Neurol, 15(12):1273-84.
6. Bickel KD (2010). Educational Objectives. J Hand Surg Am, 35(1):147-52.
7. Burton C, Chesterton LS, Davenport G (2014). Diagnosing and managing carpal tunnel syndrome in primary care. Br J Gen Pract, 64(622):262-3.
8. Tservinioti Ch, Trevlaki E, Chalkia A, et al (2023). The efficacy of physical therapy interventions in carpal tunnel syndrome: A narrative review. International Journal of Orthopaedics Sciences, 9(2): 352-357.
9. Moosazadeh M, Asadi-Aliabadi M, Rostami F, et al (2018). Prevalence of carpal tunnel syndrome in Iran: A systematic review and meta-analysis. J Mazandaran Univ Med Sci, 28(161):144-153.
10. Lozano-Calderón S, Anthony S, Ring D (2008). The quality and strength of evidence for etiology: example of carpal tunnel syndrome. J Hand Surg Am, 33(4):525-38.
11. Shiri R (2014). Hypothyroidism and carpal tunnel syndrome: A meta‐analysis. Muscle Nerve, 50(6):879-83.
12. Wiberg A, Ng M, Schmid AB, et al (2019). A genome-wide association analysis identifies 16 novel susceptibility loci for carpal tunnel syndrome. Nat Commun, 10(1):1030.
13. Werner RA, Andary M (2002). Carpal tunnel syndrome: pathophysiology and clinical neurophysiology. Clin Neurophysiol, 113(9):1373-81.
14. Camara-Lemarroy CR, Gonzalez-Moreno EI, Guzman-de la Garza FJ, et al (2012). Arachidonic acid derivatives and their role in peripheral nerve degeneration and regeneration. ScientificWorldJournal, 2012: 168953
15. Phillis JW, Horrocks LA, Farooqui AA (2006). Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Res Rev, 52(2):201-43.
16. Williams C (1971). Aspects of tyrosine metabolism in schizophrenia. Psychol Med, 1(4):286-91.
17. Norwood S, Liao J, Hammock BD, Yang G-Y (2010). Epoxyeicosatrienoic acids and soluble epoxide hydrolase: potential therapeutic targets for inflammation and its induced carcinogenesis. Am J Transl Res, 2(4):447-57.
18. Bryda J, Watroba S (2018). The proinflammatory role of lipoxygenases in rheumatoid arthritis. J Pre Clin Clin Res, 12(4):129-134.
19. Horrobin DF (1993). Fatty acid metabolism in health and disease: the role of Δ-6-desaturase. Am J Clin Nutr, 57(5 Suppl):732S-736S;
20. Van Doormaal J, Idema I, Muskiet F, et al (1988). Effects of short-term high dose intake of evening primrose oil on plasma and cellular fatty acid compositions, α-tocopherol levels, and erythropoiesis in normal and type 1 (insulin-dependent) diabetic men. Diabetologia, 31(8):576-84.
21. Tilvis R, Helve E, Miettinen T (1986). Improvement of diabetic control by continuous subcutaneous insulin infusion therapy changes fatty acid composition of serum lipids and erythrocytes in type 1 (insulin-dependent) diabetes. Diabetologia, 29(10):690-4.
22. Magy N, Liepnieks JJ, Gil H, Kantelip B, et al (2003). A transthyretin mutation (Tyr78Phe) associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis. Amyloid, 10(1):29-33.
23. Austin PJ, Moalem-Taylor G (2010). The neuro-immune balance in neuropathic pain: involvement of inflammatory immune cells, immune-like glial cells and cytokines. J Neuroimmunol, 229(1-2):26-50.
24. Lees JG, Fivelman B, Duffy SS, et al (2015). Cytokines in neuropathic pain and associated depression. Mod Trends Pharmacopsychiatry, 30:51-66.
25. Moalem-Taylor G, Baharuddin B, Bennett B, et al (2017). Immune dysregulation in patients with carpal tunnel syndrome. Sci Rep, 7(1):8218.
26. Schmid AB, Nee RJ, Coppieters MW (2013). Reappraising entrapment neuropathies–mechanisms, diagnosis and management. Man Ther, 18(6):449-57.
27. Grosser T, Ricciotti E, FitzGerald GA (2017). The cardiovascular pharmacology of nonsteroidal anti-inflammatory drugs. Trends Pharmacol Sci, 38(8):733-48.
28. Sala A, Proschak E, Steinhilber D, Rovati GE (2018). Two-pronged approach to anti-inflammatory therapy through the modulation of the arachidonic acid cascade. Biochem Pharmacol, 158:161-73.
29. Cheng L, Cao W, Behar J, et al (2005). Inflammation induced changes in arachidonic acid metabolism in cat LES circular muscle. Am J Physiol Gastrointest Liver Physiol, 288(4):G787-97.
30. Calabrese C, Triggiani M, Marone G, Mazzarella G (2000). Arachidonic acid metabolism in inflammatory cells of patients with bronchial asthma. Allergy, 55 Suppl 61:27-30.
31. Bassaganya-Riera J, Hontecillas R, Zimmerman DR, Wannemuehler MJ (2001). Dietary conjugated linoleic acid modulates phenotype and effector functions of porcine CD8+ lymphocytes. J Nutr, 131(9):2370-7.
32. Hayek MG, Han SN, Wu D, et al (1999). Dietary conjugated linoleic acid influences the immune response of young and old C57BL/6NCrlBR mice. J Nutr, 129(1):32-8.
33. Yang M, Pariza MW, Cook ME (2000). Dietary conjugated linoleic acid protects against end stage disease of systemic lupus erythematosus in the NZB/W F1 mouse. Immunopharmacol Immunotoxicol, 22(3):433-49.
34. Cook M, Miller C, Park Y, Pariza M (1993). Immune modulation by altered nutrient metabolism: nutritional control of immune-induced growth depression. Poult Sci, 72(7):1301-5.
35. Hontecillas R, Wannemeulher MJ, Zimmerman DR, et al (2002). Nutritional regulation of porcine bacterial-induced colitis by conjugated linoleic acid. J Nutr, 132(7):2019-27.
36. Li Y, Watkins BA (1998). Conjugated linoleic acids alter bone fatty acid composition and reduce ex vivo prostaglandin E 2 biosynthesis in rats fed n-6 or n-3 fatty acids. Lipids, 33(4):417-25.
37. Erdinest N, Shmueli O, Grossman Y, et al (2012). Anti-inflammatory effects of alpha linolenic acid on human corneal epithelial cells. Invest Ophthalmol Vis Sci, 53(8):4396-406.
38. Reilly MP, Lawson JA, FitzGerald GA (1998). Eicosanoids and isoeicosanoids: indices of cellular function and oxidant stress. J Nutr, 128(2 Suppl):434S-438S.
39. Nevalainen T, Aho H, Peuravuori H (1994). Secretion of group 2 phospholipase A2 by lacrimal glands. Invest Ophthalmol Vis Sci, 35(2):417-21.
40. Nevalainen T, Meri KM, Niemi M (1993). Synovial‐type (group II) phospholipase A2 human seminal plasma. Andrologia, 25(6):355-8.
41. Touqui L, Alaoui-El-Azher M (2001). Mammalian secreted phospholipases a2 and their pathophysiolo-gical significance in inflammatory diseases. Curr Mol Med, 1(6):739-54.
42. Kugiyama K, Ota Y, Sugiyama S, et al (2000). Prognostic value of plasma levels of secretory type II phospholipase A2 in patients with unstable angina pectoris. Am J Cardiol, 86(7):718-22.
43. Miki Y, Yamamoto K, Taketomi Y, et al (2013). Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators. J Exp Med, 210(6):1217-34.
44. Hoeft B, Linseisen J, Beckmann L, et al (2010). Polymorphisms in fatty acid metabolism-related genes are associated with colorectal cancer risk. Carcinogenesis, 31(3):466-72.
45. Ray U, Roy D, Jin L, et al (2021). Group III phospholipase A2 downregulation attenuated survival and metastasis in ovarian cancer and promotes chemo-sensitization. J Exp Clin Cancer Res, 40(1):182.
46. Shao S, Chen J, Swindell WR, et al (2021). Phospholipase A2 enzymes represent a shared pathogenic pathway in psoriasis and pityriasis rubra pilaris. JCI Insight, 6(20): e151911.
47. Dykes IM, Emanueli C (2017). Transcriptional and post-transcriptional gene regulation by long non-coding RNA. Genomics Proteomics Bioinformatics, 15(3):177-186.
48. Malakootian M, Gholipour A, Bagheri Moghaddam M, et al (2022). Potential roles of circular rnas and environmental and clinical factors in intervertebral disc degeneration. Environ Health Eng Manag, 9(2):189-200.
49. Taheri Bajgan E, Gholipour A, Faghihi M, et al (2022). Linc-ROR has a Potential ceRNA Activity for OCT4A by Sequestering miR-335-5p in the HEK293T Cell Line. Biochem Genet, 60:1007–1024.
| Files | ||
| Issue | Vol 53 No 8 (2024) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v53i8.16293 | |
| Keywords | ||
| Carpal tunnel syndrome RNA sequencing Signaling pathways Noncoding RNAs | ||
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How to Cite
1.
Oveisee M, Gholipour A, Bagheri Moghadam M, Malakootian M. Bioinformatics Analysis of Differentially Expressed Genes in Carpal Tunnel Syndrome Using RNA Sequencing. Iran J Public Health. 2024;53(8):1871-1882.
