The Common H202D Variant in GDF-15 Does Not Affect Its Bioactivity but Can Significantly Interfere with Measurement of Its Circulating Levels.
Authors
Karusheva, Yanislava
Ratcliff, Matthew
Mörseburg, Alexander
Barker, Peter
Burling, Keith
Backmark, Anna
Roth, Robert
Jermutus, Lutz
Guiu-Jurado, Esther
Blüher, Matthias
Hyvönen, Marko
Publication Date
2022-10-29Journal Title
J Appl Lab Med
ISSN
2576-9456
Publisher
Oxford University Press (OUP)
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Karusheva, Y., Ratcliff, M., Mörseburg, A., Barker, P., Melvin, A., Sattar, N., Burling, K., et al. (2022). The Common H202D Variant in GDF-15 Does Not Affect Its Bioactivity but Can Significantly Interfere with Measurement of Its Circulating Levels.. J Appl Lab Med https://doi.org/10.1093/jalm/jfac055
Abstract
BACKGROUND: There is growing interest in the measurement of growth differentiation factor 15 (GDF-15) in a range of disorders associated with cachexia. We undertook studies to determine whether a common histidine (H) to aspartate (D) variant at position 202 in the pro-peptide (position 6 in the mature peptide) interfered with its detection by 3 of the most commonly used immunoassays. METHODS: Three synthetic GDF-15-forms (HH homo-, HD hetero-, and DD-homodimers) were measured after serial dilution using Roche Elecsys®, R&D QuantikineTM ELISA, and MSD R&D DuoSet® immunoassays. GDF-15 concentrations were measured by the Roche and the MSD R&D immunoassays in 173 genotyped participants (61 HH homozygotes, 59 HD heterozygotes, and 53 DD homozygotes). For the comparative statistical analyses of the GDF-15 concentrations, we used non-parametric tests, in particular Bland-Altman difference (bias) plots and Passing-Bablok regression. The bioactivity of the 2 different homodimers was compared in a cell-based assay in HEK293S-SRF-RET/GFRAL cells. RESULTS: The Roche assay detected H- and D-containing peptides similarly but the R&D reagents (Quantikine and DuoSet) consistently underreported GDF-15 concentrations in the presence of the D variant. DD dimers had recoveries of approximately 45% while HD dimers recoveries were 62% to 78%. In human serum samples, the GDF-15 concentrations reported by the R&D assay were a median of 4% lower for HH, a median of 36% lower for HD, and a median of 61% lower for DD compared to the Roche assay. The bioactivities of the HH and DD peptides were indistinguishable. CONCLUSIONS: The D variant of GDF-15 substantially affects its measurement by a commonly used immunoassay, a finding that has clear implications for its interpretation in research and clinical settings.
Keywords
Humans, Growth Differentiation Factor 15, Immunoassay, Enzyme-Linked Immunosorbent Assay
Sponsorship
MRC (MC_UU_00014/1)
MRC (MC_UU_00014/5)
Embargo Lift Date
2023-07-07
Identifiers
External DOI: https://doi.org/10.1093/jalm/jfac055
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337923
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