Latent autoimmune diabetes in adults (LADA) shares immunological and genetic features with type 1 diabetes but is frequently misclassified as type 2 diabetes mellitus (T2DM) in clinical practice because of overlapping metabolic characteristics. A proteome-wide Mendelian randomization (MR) and observational clinical analysis published in Cardiovascular Diabetology evaluated plasma protein biomarkers associated with LADA and their potential ability to distinguish LADA from T2DM.
The analysis incorporated cis-protein quantitative trait loci (cis-pQTL) data for 1,389 plasma proteins from the deCODE cohort involving 35,559 participants and genome-wide association study (GWAS) data including 2,634 individuals with LADA and 5,947 controls of European ancestry. In a second-stage observational analysis, CXCL10 plasma levels were measured using enzyme-linked immunosorbent assay (ELISA) in a matched Chinese cohort involving 241 participants with LADA, T2DM, or healthy controls.
Genetically predicted higher plasma CXCL10 levels were associated with increased LADA risk (OR 5.49 per 1-standard deviation increase; 95% CI, 1.74-17.32). Associations with LADA were also observed for serum amyloid A1 (SAA1; OR 1.28, 95% CI, 1.14-1.45) and serum amyloid A2 (SAA2; OR 1.22, 95% CI, 1.11-1.34). Replication analyses and multivariable MR further supported the association between CXCL10 and LADA.
In the observational cohort, CXCL10 differentiated LADA from healthy controls with receiver operating characteristic area under the curve (ROC-AUC) and precision-recall area under the curve (PR-AUC) values of 0.889 and 0.919, respectively. CXCL10 also differentiated LADA from T2D, with ROC-AUC and PR-AUC values of 0.838 and 0.921. Druggability analyses indicated that CXCL10 is being investigated as a potential therapeutic target, while phenome-wide MR across 1,006 diseases and traits did not identify major safety concerns related to its use as a biomarker.
The findings support the potential diagnostic relevance of CXCL10 in distinguishing LADA from T2DM.
