Identifizierung von Phänotypen, die mit Genen von metabolischer Relevanz assoziiert sind
Zusammenfassung der Projektergebnisse
Genetic variants in proteins can interfere with measurement of their circulating concentrations. Given the growing biomedical importance of GDF15, we wished to establish whether a common histidine to aspartate variant present in position 6 of the mature GDF15 protein (H6D variant) interfered with its measurement by commonly used immuno-assays. We first examined the detectability of recombinant monomers, homodimers and heterodimers of GDF15 by reagents used in two widely used immunoassays (Roche Elecsys® GDF-15 and the R&D Quantikine assay). The Roche assay detected the H and D containing peptides similarly but the R&D reagents consistently underreported concentrations of the D-containing peptide by as much as 50% in the case of D-containing homodimers. Measurements of plasma levels by the two assays in genotyped human participants showed that the R&D reagents reported values in heterozygotes that were ~25% lower, and in homozygotes, 50% lower than the Roche assay. We finally studied the activation of the GDF 15 receptor, GFRAL-Ret, in a cell based assay and found that the activities of the HH and DD containing GDF15 peptide were indistinguishable. These results have implications for the interpretation of genetic epidemiological studies which have used the R&D reagents to measure GDF15 and for the emerging clinical use of GDF15 as a diagnostic and prognostic biomarker. We provide a correction factor which may be of some utility for the analysis of data generated with the R&D reagents where genotype of the participants is known.
Projektbezogene Publikationen (Auswahl)
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The Common H202D Variant in GDF-15 Does Not Affect Its Bioactivity but Can Significantly Interfere with Measurement of Its Circulating Levels. The Journal of Applied Laboratory Medicine, 7(6), 1388-1400.
Karusheva, Yanislava; Ratcliff, Matthew; Mörseburg, Alexander; Barker, Peter; Melvin, Audrey; Sattar, Naveed; Burling, Keith; Backmark, Anna; Roth, Robert; Jermutus, Lutz; Guiu-Jurado, Esther; Blüher, Matthias; Welsh, Paul; Hyvönen, Marko & O.’Rahilly, Stephen
