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. 2022 Feb;298(2):101575.
doi: 10.1016/j.jbc.2022.101575. Epub 2022 Jan 8.

Analysis of normal levels of free glycosaminoglycans in urine and plasma in adults

Sinisa Bratulic  1 , Angelo Limeta  1 , Francesca Maccari  2 , Fabio Galeotti  2 , Nicola Volpi  2 , Max Levin  3 , Jens Nielsen  4 , Francesco Gatto  5
Affiliations

Analysis of normal levels of free glycosaminoglycans in urine and plasma in adults

Sinisa Bratulic et al. J Biol Chem. 2022 Feb.

Abstract

Plasma and urine glycosaminoglycans (GAGs) are long, linear sulfated polysaccharides that have been proposed as potential noninvasive biomarkers for several diseases. However, owing to the analytical complexity associated with the measurement of GAG concentration and disaccharide composition (the so-called GAGome), a reference study of the normal healthy GAGome is currently missing. Here, we prospectively enrolled 308 healthy adults and analyzed their free GAGomes in urine and plasma using a standardized ultra-high-performance liquid chromatography coupled with triple-quadrupole tandem mass spectrometry method together with comprehensive demographic and blood chemistry biomarker data. Of 25 blood chemistry biomarkers, we mainly observed weak correlations between the free GAGome and creatinine in urine and hemoglobin or erythrocyte counts in plasma. We found a higher free GAGome concentration - but not a more diverse composition - in males. Partitioned by gender, we also established reference intervals for all detectable free GAGome features in urine and plasma. Finally, we carried out a transference analysis in healthy individuals from two distinct geographical sites, including data from the Lifelines Cohort Study, which validated the reference intervals in urine. Our study is the first large-scale determination of normal free GAGomes reference intervals in plasma and urine and represents a critical resource for future physiology and biomarker research.

Keywords: GAGome; biomarkers; chondroitin sulfate; glycosaminoglycans; heparan sulfate; hyaluronic acid; reference intervals.

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Conflict of interest statement

Conflict of interest The authors declare the following conflicts of interest with the contents of this article: at study start, J. N. and Fr. G. were listed as co-inventors in patent applications related to the biomarkers described in this study. At the time of submission, J. N. and Fr. G. were shareholders in Elypta AB, which owned the above-mentioned patent applications, J. N. was member of the board and Fr. G. was an employee in Elypta AB. All other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Totalfreechondroitin sulfate (CS) and heparan sulfate (HS) concentration (μg/ml), charge, and disaccharide concentration (μg/ml) and composition (in mass fraction %) in theurine of thereference sample group by gender (Cohort 1 and 2, Nfemales= 188 Nmales= 120). The error bars indicate ± 1 SD. Key: Red – female, blue - male.
Figure 2
Figure 2
Totalfreechondroitin sulfate (CS) concentration (μg/ml), charge, and disaccharide concentration (μg/ml) and composition (in mass fraction %) inthe plasma ofthe reference sample group (Cohort 1 and 2). Free HS was undetectable in plasma. The error bars indicate ± 1 SD. Key: Red – female, blue - male. HS, heparan sulfate.
See this image and copyright information in PMC

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