The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis

Ekrem AKBULUT, (Malatya Turgut Özal Üniversitesi, Mühendislik ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü, Malatya, Türkiye)
Servet YOLBAŞ, (İnönü Üniversitesi, Tıp Fakültesi, Romatoloji Anabilim Dalı, Malatya, Türkiye)
Metin ÖZGEN (Ondokuz Mayıs Üniversitesi, Tıp Fakültesi, Romatoloji Anabilim Dalı, Samsun, Türkiye)
Türk Biyokimya Dergisi
1 0
Yıl: 2022 Cilt: 47 Sayı: 1 Sayfa Aralığı: 103 - 111 Metin Dili: İngilizce DOI: 10.1515/tjb-2021-0086 İndeks Tarihi: 17-05-2023

The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis

Öz:
Objectives: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that mainly affects the axial skeleton. Peroxisome proliferator activated receptor alpha (PPARA) is an intracellular transcription factor, which play a role in inflammation and osteoblasting activity. This study is designed to investigate the relationship of NG_012204.2:p.Ala268Val polymorphism of PPARA with axSpA risk and its role in disease development. Methods: This study was conducted with 168 patients and 181 controls. Genotyping was done with MALDITOF. Gene expression level was analyzed by quantitative real time PCR (RT-qPCR). The protein homology models of PPARA were created with ProMod3. Ligand binding dynamics were tested using the AutoDock4 docking program. Statistical evaluations were made with SPSS (ver24) and GeneGlobe. Results: Our results showed that C>T polymorphism causing NG_012204.2:p.Ala268Val change was associated with disease risk (p=0.024) and T allele increased disease risk 1.7 times (95% CI=1.070–2.594). PPARA expression decreased (p<0.05) in individuals carrying the T allele. We determined that the ligand entry pocket was opened 1.1Åin the polymorphic PPARA. Polymorphic change caused a decrease in the ligand binding affinity. Conclusions: Our results provide an important contribution to elucidating the development of axSpA and demonstrate the potential of PPARA as a marker for the diagnosis of axSpA.
Anahtar Kelime:

Aksiyal spondiloartrit gelişiminde PPARA’nın A268V ekson-7 polimorfizminin rolü

Öz:
Amaç: Aksiyal spondiloartrit (axSpA), aksiyal iskeleti etkileyen kronik enflamatuar bir hastalıktır. Peroksizom çoğaltıcılar tarafından aktive edilen reseptör (PPARA), enflamasyon ve osteoblast aktivitede rol oynayan hücre içi bir transkripsiyon faktörüdür. Bu çalışma, PPARA’nın NG_012204.2:p.Ala268Val polimorfizminin axSpA riski ile ilişkisini ve hastalık gelişimindeki rolünü araştırmak için tasarlanmıştır. Yöntem: Bu çalışma 168 hasta ve 181 kontrol ile yürütüldü. Genotipleme MALDITOF ile yapıldı. Gen ekspresyon seviyesi nicel gerçek zamanlı PCR (RT-qPCR) ile analiz edildi. PPARA’nın protein homoloji modelleri ProMod3 ile oluşturuldu. Ligand bağlanma dinamikleri, AutoDock4 yerleştirme programı kullanılarak test edildi. İstatistiksel değerlendirmeler SPSS (ver24) ve GeneGlobe ile yapıldı. Tartışma: Sonuçlarımız, NG_012204.2:p.Ala268Val değişikliğine neden olan C>T polimorfizminin hastalık riski ile ilişkili olduğunu (p=0.024) ve T allelinin hastalık riskini 1.7 kat arttırdığını (%95CI=1.070–2.594) gösterdi. T allelini taşıyan bireylerde PPARA ekspresyonu azaldı (p<0.05). Polimorfik PPARA’da ligand giriş cebinin 1.1 Â açıldığını belirledik. Polimorfik değişiklik, ligand bağlanma afinitesinde bir azalmaya neden oldu. Sonuç: Sonuçlarımız, axSpA’in gelişim mekanizmasını aydınlatmaya önemli bir katkı sağlar ve PPARA’nın axSpA tanısı için bir belirteç olarak potansiyelini göstermektedir.
Anahtar Kelime:

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık
  • 1. Sharma SM, Choi D, Planck SR, Harrington CA, Austin CR, Lewis JA, et al. Insights in to the pathogenesis of axial spondyloarthropathy based on gene expression profiles. Arthritis Res Ther 2009;11: R168.
  • 2. Zhao J, Huang C, Huang H, Pan J-K, Zeng L-F, Luo M-H, et al. Prevalence of ankylosing spondylitis in a Chinese population: a systematic review and meta-analysis. Rheumatol Int 2020;40: 859–72.
  • 3. Dean LE, Jones GT, Macdonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis. Rheumatol 2014;53:650–7.
  • 4. Sieper J, Poddubnyy D. Axial spondyloarthritis. The Lancet; 2017. [Online] 2017.
  • 5. Poddubnyy D, Sieper J. Mechanismof new bone formation in axial spondyloarthritis. Curr Rheumatol Rep 2017;19:1–9.
  • 6. Ramiro S, Van Tubergen A, Stolwijk C, van der Heijde D, Royston P, Landew´e R. Reference intervals of spinal mobility measures in normal individuals: the mobility study. Ann Rheum Dis 2015;74: 1218–24.
  • 7. Castro-Zunti R, Park EH, Choi Y, Jin GY, Ko S-b. Early detection of ankylosing spondylitis using texture features and statistical machine learning, and deep learning, with some patient age analysis. Comput Med Imaging Graph 2020;82:101718.
  • 8. Yi E, Ahuja A, Rajput T, George AT, Park Y. Clinical, economic, and humanistic burden associated with delayed diagnosis of axial spondyloarthritis: a systematic review. Rheumatol Ther 2020;7: 65–87.
  • 9. Wang R, Ward MM. Epidemiology of axial spondyloarthritis: an update. Curr Opin Rheumatol 2018;30:137–43.
  • 10. Carvalho PD, Machado PM. How to investigate: early axial spondyloarthritis. Best Pract Res Clin Rheumatol 2019;33: 101427.
  • 11. Bougarne N, Mylka V, Ratman D, Beck IM, Thommis J, De Cauwer L, et al. Mechanisms underlying the functional cooperation between PPARalpha and GRalpha to attenuate inflammatory responses. Front Immunol 2019;10:1–14.
  • 12. Silva AKS, Peixoto CA. Role of peroxisome proliferator-activated receptors in non-alcoholic fatty liver disease inflammation. Cell Mol Life Sci 2018;75:2951–61.
  • 13. Ahmed W, Ziouzenkova O, Brown J, Devchand P, Francis S, Kadakia M, et al. PPARs and their metabolic modulation: new mechanisms for transcriptional regulation? J Intern Med 2007; 262:184–98.
  • 14. Ramanan S, Zhao W, Riddle DR, Robbins ME. Review article: role of PPARs in radiation-induced brain injury. PPAR Res 2010;2010: 1–12.
  • 15. Hill MR, Clarke S, Rodgers K, Thornhill B, Peters JM, Gonzalez FJ, et al. Effect of peroxisome proliferator-activated receptor alpha activators on tumor necrosis factor expression in mice during endotoxemia. Infect Immun Am Soc Microbiol 1999;67:3488–93.
  • 16. O’Rielly DD, Zhai G, Rahman P. Expression and metabolomic profiling in axial spondyloarthritis. Curr Rheumatol Rep 2018; 20:51.
  • 17. Costantino F, Breban M, Garchon HJ. Genetics and functional genomics of spondyloarthritis. Front Immunol 2018;9:2933.
  • 18. Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, et al. Swiss-Model: homology modelling of protein structures and complexes. Nucleic Acids Res 2018;46: W296–303.
  • 19. Kumar S, Stecher G, Li M, Knyaz C, Tamura K. MEGA X: molecular evolutionary genetics analysis across computing platforms. Mol Biol Evol 2018;35:1547–9.
  • 20. Wiederstein M, Sippl MJ. ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 2007;35:407–10.
  • 21. Chen VB, Arendall WB, Headd JJ, Keedy DA, Immormino RM, Kapral G, et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr Sect D Biol Crystallogr 2010;66:12–21.
  • 22. Zhang Y, Skolnick J. Scoring function for automated assessment of protein structure template quality. Proteins Struct Funct Genet 2004;57:702–10.
  • 23. Pires DEV, Ascher DB, Blundell TL. MCSM: predicting the effects of mutations in proteins using graph-based signatures. Bioinformatics 2014;30:335–42.
  • 24. Pires DEV, Ascher DB, Blundell TL. DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res 2014;42: W314–9.
  • 25. Rodrigues CHM, Pires DEV, Ascher DB. DynaMut2: assessing changes in stability and flexibility upon single and multiple point missense mutations. Protein Sci 2021;30:60–9.
  • 26. Pandurangan AP, Ochoa-Montaño B, Ascher DB, Blundell TL. SDM: a server for predicting effects of mutations on protein stability. Nucleic Acids Res 2017;45:W229–35.
  • 27. Steffen C, Thomas K, Huniar U, Hellweg A, Rubner O, Schroer A. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 2010;31: 2967–70.
  • 28. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998;19:1639–62.
  • 29. Furst DE, Louie JS. Targeting inflammatory pathways in axial spondyloarthritis. Arthritis Res Ther 2019;21:1–15.
  • 30. Zhao SS, Robertson S, Reich T, Harrison NL,Moots RJ, Goodson NJ. Prevalence and impact of comorbidities in axial spondyloarthritis: systematic review and meta-analysis. Revmatol 2020;59: IV47–57.
  • 31. Park H, Bourla AB, Kastner DL, Colbert RA, Siegel RM. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol 2012;12:570–80.
  • 32. Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999;20: 649–88.
  • 33. Devchand PR, KellerH,Peters JM, VazquezM,Gonzalez FJ,WahliW. The PPARα-leukotriene B4 pathway to inflammation control. Nature 1996;384:39–43.
  • 34. Schett G, Rudwaleit M. Can we stop progression of ankylosing spondylitis? Best Pract Res Clin Rheumatol 2010;24:363–71.
  • 35. Akbulut E, Özgen M. Contribution of polymorphism in the noncoding region of PPARα to the development of axial spondyloarthritis. Adıyaman Univ J Sci 2020;10:55–64.
  • 36. Ralston SH, Urquhart GDK, Brzeski M, Sturrock RD. Prevalence of vertebral compression fractures due to osteoporosis in ankylosing spondylitis. Br Med J 1990;300:563–5.
  • 37. Akbulut E. Mutations in the SARS CoV-2 spike protein may cause functional changes in the protein quaternary structure. Turkish J Biochem 2021;46:137–44.
  • 38. Kamburov A, Lawrence MS, Polak P, Leshchiner I, Lage K, Golub TR, et al. Comprehensive assessment of cancer missense mutation clustering in protein structures. Proc Natl Acad Sci 2015;112: E5486–95.
  • 39. Kota BP, Huang THW, Roufogalis BD. An overview on biological mechanisms of PPARs. Pharmacol Res 2005;51:85–94.
  • 40. Kersten S, Desvergne B, Wahli W. Roles of PPARS in health and disease. Nature 2000;405:421–4.
APA AKBULUT E, Yolbas S, Ozgen M (2022). The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis. , 103 - 111. 10.1515/tjb-2021-0086
Chicago AKBULUT EKREM,Yolbas Servet,Ozgen Metin The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis. (2022): 103 - 111. 10.1515/tjb-2021-0086
MLA AKBULUT EKREM,Yolbas Servet,Ozgen Metin The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis. , 2022, ss.103 - 111. 10.1515/tjb-2021-0086
AMA AKBULUT E,Yolbas S,Ozgen M The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis. . 2022; 103 - 111. 10.1515/tjb-2021-0086
Vancouver AKBULUT E,Yolbas S,Ozgen M The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis. . 2022; 103 - 111. 10.1515/tjb-2021-0086
IEEE AKBULUT E,Yolbas S,Ozgen M "The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis." , ss.103 - 111, 2022. 10.1515/tjb-2021-0086
ISNAD AKBULUT, EKREM vd. "The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis". (2022), 103-111. https://doi.org/10.1515/tjb-2021-0086
APA AKBULUT E, Yolbas S, Ozgen M (2022). The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis. Türk Biyokimya Dergisi, 47(1), 103 - 111. 10.1515/tjb-2021-0086
Chicago AKBULUT EKREM,Yolbas Servet,Ozgen Metin The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis. Türk Biyokimya Dergisi 47, no.1 (2022): 103 - 111. 10.1515/tjb-2021-0086
MLA AKBULUT EKREM,Yolbas Servet,Ozgen Metin The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis. Türk Biyokimya Dergisi, vol.47, no.1, 2022, ss.103 - 111. 10.1515/tjb-2021-0086
AMA AKBULUT E,Yolbas S,Ozgen M The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis. Türk Biyokimya Dergisi. 2022; 47(1): 103 - 111. 10.1515/tjb-2021-0086
Vancouver AKBULUT E,Yolbas S,Ozgen M The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis. Türk Biyokimya Dergisi. 2022; 47(1): 103 - 111. 10.1515/tjb-2021-0086
IEEE AKBULUT E,Yolbas S,Ozgen M "The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis." Türk Biyokimya Dergisi, 47, ss.103 - 111, 2022. 10.1515/tjb-2021-0086
ISNAD AKBULUT, EKREM vd. "The role of A268V exon-7 polymorphism of PPARA in development of axial spondyloarthritis". Türk Biyokimya Dergisi 47/1 (2022), 103-111. https://doi.org/10.1515/tjb-2021-0086
Sayfa Oluşturulma Tarihi
24-04-2024 7:8

İLETİŞİM

TÜBİTAK ULAKBİM TR Dizin

Yüzüncüyıl, İşçi Blokları Mahallesi

Muhsin Yazıcıoğlu Caddesi No:51/C

06530 Çankaya / ANKARA +90 (312) 298 92 00

trdizin@tubitak.gov.tr

TÜBİTAK ULAKBİM Ulusal Akademik Ağ ve Bilgi Merkezi Cahit Arf Bilgi Merkezi © Tüm Hakları Saklıdır. Gizlilik Politikası Kullanım Şartları