Common H202D variant in GDF-15 does not affect its bioactivity but can significantly interfere with measurement of its circulating levels

Karusheva, Y. et al. (2022) Common H202D variant in GDF-15 does not affect its bioactivity but can significantly interfere with measurement of its circulating levels. Journal of Applied Laboratory Medicine, 7(6), pp. 1388-1400. (doi: 10.1093/jalm/jfac055) (PMID:35796717)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Welsh, Professor Paul and Sattar, Professor Naveed
• Authors: Karusheva, Y., Ratcliff, M., Mörseburg, A., Barker, P., Melvin, A., Sattar, N., Burling, K., Backmark, A., Roth, R., Jermutus, L., Guiu-Jurado, E., Blueher, M., Welsh, P., Hyvönen, M., and O’Rahilly, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of Applied Laboratory Medicine
• Publisher: Oxford University Press
• ISSN: 2576-9456
• ISSN (Online): 2475-7241
• Published Online: 07 July 2022
• Copyright Holders: Copyright © 2022 American Association for Clinical Chemistry
• First Published: First published in Journal of Applied Laboratory Medicine 7(6): 1388-1400
• Publisher Policy: Reproduced under a Creative Commons License