Details

Autor(en) / Beteiligte

• Luo, Hong
• Bauer, Alina
• Nano, Jana
• Petrera, Agnese
• Rathmann, Wolfgang
• Herder, Christian
• Hauck, Stefanie M.
• Sun, Benjamin B.
• Hoyer, Annika
• Peters, Annette
• Thorand, Barbara

Titel

Associations of plasma proteomics with type 2 diabetes and related traits: results from the longitudinal KORA S4/F4/FF4 Study

Ist Teil von

• Diabetologia, 2023-09, Vol.66 (9), p.1655-1668

Ort / Verlag

Berlin/Heidelberg: Springer Berlin Heidelberg

Erscheinungsjahr

2023

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Aims/hypothesis This study aimed to elucidate the aetiological role of plasma proteins in glucose metabolism and type 2 diabetes development. Methods We measured 233 proteins at baseline in 1653 participants from the Cooperative Health Research in the Region of Augsburg (KORA) S4 cohort study (median follow-up time: 13.5 years). We used logistic regression in the cross-sectional analysis ( n =1300), and Cox regression accounting for interval-censored data in the longitudinal analysis ( n =1143). We further applied two-level growth models to investigate associations with repeatedly measured traits (fasting glucose, 2 h glucose, fasting insulin, HOMA-B, HOMA-IR, HbA 1c ), and two-sample Mendelian randomisation analysis to investigate causal associations. Moreover, we built prediction models using priority-Lasso on top of Framingham-Offspring Risk Score components and evaluated the prediction accuracy through AUC. Results We identified 14, 24 and four proteins associated with prevalent prediabetes (i.e. impaired glucose tolerance and/or impaired fasting glucose), prevalent newly diagnosed type 2 diabetes and incident type 2 diabetes, respectively (28 overlapping proteins). Of these, IL-17D, IL-18 receptor 1, carbonic anhydrase-5A, IL-1 receptor type 2 (IL-1RT2) and matrix extracellular phosphoglycoprotein were novel candidates. IGF binding protein 2 (IGFBP2), lipoprotein lipase (LPL) and paraoxonase 3 (PON3) were inversely associated while fibroblast growth factor 21 was positively associated with incident type 2 diabetes. LPL was longitudinally linked with change in glucose-related traits, while IGFBP2 and PON3 were linked with changes in both insulin- and glucose-related traits. Mendelian randomisation analysis suggested causal effects of LPL on type 2 diabetes and fasting insulin. The simultaneous addition of 12 priority-Lasso-selected biomarkers (IGFBP2, IL-18, IL-17D, complement component C1q receptor, V-set and immunoglobulin domain-containing protein 2, IL-1RT2, LPL, CUB domain-containing protein 1, vascular endothelial growth factor D, PON3, C-C motif chemokine 4 and tartrate-resistant acid phosphatase type 5) significantly improved the predictive performance (ΔAUC 0.0219; 95% CI 0.0052, 0.0624). Conclusions/interpretation We identified new candidates involved in the development of derangements in glucose metabolism and type 2 diabetes and confirmed previously reported proteins. Our findings underscore the importance of proteins in the pathogenesis of type 2 diabetes and the identified putative proteins can function as potential pharmacological targets for diabetes treatment and prevention. Graphical Abstract