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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.