Untargeted Serum Proteomics Profiling in Female Patients with Idiopathic Scoliosis

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Patrick M. Carry Elizabeth A. Terhune Anna Monley Monika Dzieciatkowska Cambria Wethey Melissa Cuevas Nancy Hadley-Miller


Background: Idiopathic scoliosis is a common structural spine curvature of unknown etiology. Scoliosis onset and progression are likely related to the interplay between genetics and the environment. Serum protein levels are influenced by both genetic and environmental factors and thus, are a promising methodology.

Aims: We aimed to determine whether serum protein levels differed between idiopathic scoliosis cases and controls. In scoliosis cases, we also aimed to determine if protein levels were correlated with curve severity.

Methods: In the discovery population, serum blood samples were obtained from 7 females with severe scoliosis and 11 unaffected female controls. Liquid chromatography-mass spectroscopy was used to quantify protein levels. Wilcoxon rank sum tests were used to test for differences between cases and controls. Within scoliosis cases, Spearman correlation coefficients were used to test the correlation between curve severity and age-adjusted protein levels. Candidate proteins were defined as proteins that significantly differed between cases and controls and were moderately or strongly correlated with curve severity (ρ >0.30). We validated candidate proteins using the SomaScan Discovery v4.1 proteomics platform with serum from 11 females with scoliosis.

Results: In the discovery analysis, 10 proteins differed between cases and controls (p<0.05) and were correlated with protein levels (ρ =0.36-0.65). Of these candidate proteins, one protein, alpha 2-HS glycoprotein (AHSG), was significantly correlated with curve severity (p=0.0323) in the validation population. Fixed effects meta-analysis showed a strong inverse correlation between curve severity and decreasing alpha 2-HS glycoprotein levels (meta-combined ρ: -0.67, p=0.0052).

Conclusion: Alpha 2-HS glycoprotein met our criteria for significance in both the discovery and validation populations. Developing a proteomic signature for idiopathic scoliosis has important clinical implications. This study supports the feasibility of untargeted proteomics and provides evidence for the potential role of alpha 2-HS glycoprotein levels in scoliosis etiology.

Keywords: Untargeted Serum Proteomics Profiling, Idiopathic Scoliosis

Article Details

How to Cite
CARRY, Patrick M. et al. Untargeted Serum Proteomics Profiling in Female Patients with Idiopathic Scoliosis. Medical Research Archives, [S.l.], v. 12, n. 1, jan. 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/5006>. Date accessed: 03 mar. 2024. doi: https://doi.org/10.18103/mra.v12i1.5006.
Research Articles


1. Altaf F, Drinkwater J, Phan K, Cree AK. Systematic Review of School Scoliosis Screening. Spine Deform. 2017;5(5):303-309.

2. Weinstein SL, Dolan LA, Cheng JC, Danielsson A, Morcuende JA. Adolescent idiopathic scoliosis. Lancet. 2008;371(9623):1527-1537.

3. Konieczny MR, Senyurt H, Krauspe R. Epidemiology of adolescent idiopathic scoliosis. J Child Orthop. 2013;7(1):3-9.

4. Dolan LA, Donzelli S, Zaina F, Weinstein SL, Negrini S. Adolescent idiopathic scoliosis bracing success is influenced by time in brace: comparative effectiveness analysis of BrAIST and ISICO cohorts. Spine. 2020;45(17):1193-1199.

5. Dimitrijevic V, Scepanovic T, Jevtic N, et al. Application of the Schroth Method in the Treatment of Idiopathic Scoliosis: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health. 2022;19(24).

6. Asher MA, Burton DC. Adolescent idiopathic scoliosis: natural history and long term treatment effects. Scoliosis. 2006;1(1):2.

7. Brandwijk AC, Heemskerk JL, Willigenburg NW, Altena MC, Kempen DHR. Health-related quality of life of adult, non-surgically treated patients with idiopathic scoliosis and curves above 45 degrees : a cross-sectional study at an average follow-up of 30 years. Eur Spine J. 2023;32(9):3084-3093.

8. Danielsson AJ, Nachemson AL. Radiologic findings and curve progression 22 years after treatment for adolescent idiopathic scoliosis: comparison of brace and surgical treatment with matching control group of straight individuals. Spine (Phila Pa 1976). 2001;26(5):516-525.

9. Pehrsson K, Larsson S, Oden A, Nachemson A. Long-term follow-up of patients with untreated scoliosis. A study of mortality, causes of death, and symptoms. Spine (Phila Pa 1976). 1992;17(9):1091-1096.

10. Weinstein SL, Dolan LA, Spratt KF, Peterson KK, Spoonamore MJ, Ponseti IV. Health and function of patients with untreated idiopathic scoliosis: a 50-year natural history study. JAMA. 2003;289(5):559-567.

11. Kobayashi K, Sato K, Ando T, Imagama S. Changes in medical costs for adolescent idiopathic scoliosis over the past 15 years. Nagoya J Med Sci. 2023;85(2):333-342.

12. Bozzio AE, Hu X, Lieberman IH. Cost and Clinical Outcome of Adolescent Idiopathic Scoliosis Surgeries-Experience From a Nonprofit Community Hospital. Int J Spine Surg. 2019;13(5):474-478.

13. Simony A, Carreon LY, K HJ, Kyvik KO, Andersen MO. Concordance Rates of Adolescent Idiopathic Scoliosis in a Danish Twin Population. Spine (Phila Pa 1976). 2016;41(19):1503-1507.

14. Cheng T, Einarsdottir E, Kere J, Gerdhem P. Idiopathic scoliosis: a systematic review and meta-analysis of heritability. EFORT Open Rev. 2022;7(6):414-421.

15. Tang NL, Yeung HY, Hung VW, et al. Genetic epidemiology and heritability of AIS: A study of 415 Chinese female patients. J Orthop Res. 2012;30(9):1464-1469.

16. Ward K, Ogilvie J, Argyle V, et al. Polygenic inheritance of adolescent idiopathic scoliosis: a study of extended families in Utah. Am J Med Genet A. 2010;152A(5):1178-1188.

17. Terhune E, Heyn P, Piper C, et al. Association between genetic polymorphisms and risk of adolescent idiopathic scoliosis in case-control studies: a systematic review. J Med Genet. 2023.

18. De Salvatore S, Ruzzini L, Longo UG, et al. Exploring the association between specific genes and the onset of idiopathic scoliosis: a systematic review. BMC Med Genomics. 2022;15(1):115.

19. Kou I, Watanabe K, Takahashi Y, et al. A multi-ethnic meta-analysis confirms the association of rs6570507 with adolescent idiopathic scoliosis. Sci Rep. 2018;8(1):11575.

20. Sharma S, Gao X, Londono D, et al. Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes. Hum Mol Genet. 2011;20(7):1456-1466.

21. Takahashi Y, Kou I, Takahashi A, et al. A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat Genet. 2011;43(12):1237-1240.

22. Nelson LM, Chettier R, Ogilvie JW, Ward K. Candidate Genes for Susceptibility of Adolescent Idiopathic Scoliosis Identified Through a Large Genome-Wide Association Study. Scoliosis Research Society 46th Annual Meeting & Course; 2011; Louisville, KY.

23. Kou I, Takahashi Y, Johnson TA, et al. Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nature genetics. 2013;45(6):676-679.

24. Miyake A, Kou I, Takahashi Y, et al. Identification of a susceptibility locus for severe adolescent idiopathic scoliosis on chromosome 17q24.3. PloS one. 2013;8(9):e72802.

25. Zhu Z, Tang NL, Xu L, et al. Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls. Nature communications. 2015;6:8355.

26. Ogura Y, Kou I, Miura S, et al. A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis. American journal of human genetics. 2015;97(2):337-342.

27. Sharma S, Londono D, Eckalbar WL, et al. A PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females. Nature communications. 2015;6:6452.

28. Kou I, Otomo N, Takeda K, et al. Genome-wide association study identifies 14 previously unreported susceptibility loci for adolescent idiopathic scoliosis in Japanese. Nature communications. 2019;10(1):3685.

29. Arpon A, Milagro FI, Ramos-Lopez O, et al. Methylome-Wide Association Study in Peripheral White Blood Cells Focusing on Central Obesity and Inflammation. Genes (Basel). 2019;10(6).

30. Grauers A, Rahman I, Gerdhem P. Heritability of scoliosis. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. 2012;21(6):1069-1074.

31. Gorman KF, Julien C, Moreau A. The genetic epidemiology of idiopathic scoliosis. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. 2012;21(10):1905-1919.

32. Rotunno MS, Lane M, Zhang W, et al. Cerebrospinal fluid proteomics implicates the granin family in Parkinson's disease. Sci Rep. 2020;10(1):2479.

33. Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. 2016;15(7):673-684.

34. Yazdanpanah N, Yazdanpanah M, Wang Y, et al. Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian Randomization Study. Diabetes Care. 2022;45(1):169-177.

35. Liu M, Dongre A. Proper imputation of missing values in proteomics datasets for differential expression analysis. Brief Bioinform. 2021;22(3).

36. Huber W, von Heydebreck A, Sultmann H, Poustka A, Vingron M. Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics. 2002;18 Suppl 1:S96-104.

37. Gold L, Ayers D, Bertino J, et al. Aptamer-based multiplexed proteomic technology for biomarker discovery. PLoS One. 2010; 5(12):e15004.

38. Viechtbauer W. Conducting meta-analyses in R with the metafor package. Journal of statistical software. 2010;36:1-48.

39. Brylka L, Jahnen-Dechent W. The role of fetuin-A in physiological and pathological mineralization. Calcif Tissue Int. 2013; 93(4):355-364.

40. Chekol Abebe E, Tilahun Muche Z, Behaile TMA, et al. The structure, biosynthesis, and biological roles of fetuin-A: A review. Front Cell Dev Biol. 2022;10:945287.

41. Szweras M, Liu D, Partridge EA, et al. alpha 2-HS glycoprotein/fetuin, a transforming growth factor-beta/bone morphogenetic protein antagonist, regulates postnatal bone growth and remodeling. J Biol Chem. 2002;277(22):19991-19997.

42. Seto J, Busse B, Gupta HS, et al. Accelerated growth plate mineralization and foreshortened proximal limb bones in fetuin-A knockout mice. PLoS One. 2012; 7(10):e47338.

43. Kumbla L, Bhadra S, Subbiah MT. Multifunctional role for fetuin (fetal protein) in lipid transport. FASEB J. 1991;5(14):2971-2975.

44. Otomo N, Khanshour AM, Koido M, et al. Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study. Front Endocrinol (Lausanne). 2023;14:1089414.

45. Sun ZJ, Jia HM, Qiu GX, et al. Identification of candidate diagnostic biomarkers for adolescent idiopathic scoliosis using UPLC/QTOF-MS analysis: a first report of lipid metabolism profiles. Sci Rep. 2016;6:22274.

46. Wang Z, Huang X, Tan H, Liang J, Li Z, Shen J. Proteomic Comparison of Paraspinal Muscle Imbalance Between Idiopathic Scoliosis and Congenital Scoliosis. Neurospine. 2023; 20(2):709-724.

47. Makino H, Seki S, Kitajima I, et al. Differential proteome analysis in adolescent idiopathic scoliosis patients with thoracolumbar/lumbar curvatures. BMC Musculoskelet Disord. 2019;20(1):247.

48. Wang Q, Wang C, Liu J, Sun J, Wang C, Zhang X. Plasma proteomics analysis of adolescent idiopathic scoliosis patients revealed by Quadrupole-Orbitrap mass spectrometry. Proteomics Clin Appl. 2021;15(4):e2100002.

49. Eigenbrot C. Structure, function, and activation of coagulation factor VII. Curr Protein Pept Sci. 2002;3(3):287-299