Identifying molecular pathways of type 2 diabetes using proteomics, metabolic, and anthropometric profiles in UK and Chinese adults

IntroductionProteogenomic analyses in large biobanks provide opportunities to improve understanding of the aetiology of type 2 diabetes (T2D) and to identify potential therapeutic targets. MethodsWe identified proteins (Olink Explore) associated with glycaemic traits and/or T2D with observational designs in UK Biobank (UKB-EUR, n =33,301). Bayesian non-negative matrix factorisation (bNMF) was applied to cluster T2D-associated proteins incorporating their phenotypic associations with 43 metabolic/anthropometric traits. For clusters leading proteins (top 10% by ranking), two-steps colocalization and bidirectional Mendelian randomization were performed to investigate three-way (i.e., protein-metabolic/anthropometric traits-T2D) relationships. Equivalent genetic analyses were conducted in the China Kadoorie Biobank (CKB-EAS, n = 2,029) to evaluate shared and ancestry-specific findings. ResultsA total of 1,793 proteins were observationally associated with glycaemic traits and/or T2D in UKB-EUR. Using bNMF, these proteins were classified into five clusters (Adiposity, Reduced adiposity, Lipids, Liver, and Kidney), of which the Reduced adiposity and Kidney clusters were novel; 906 proteins were identified as cluster-leading. Triangulation of observational and genetic evidence identified five proteins (B4GAT1, DNER, ENO3, HMOX2, OMG) potentially affecting T2D in UKB-EUR, one (ENTR1) in CKB-EAS, and three (RTBDN, TSPAN8, NCR3LG1) in both populations. In UKB-EUR, six proteins (CD34, FGFBP3, GALNT10, KHK, MENT, MXRA8) appeared to be consequences of T2D, while five proteins (GSTA1, GSTA3, MEGF9, NCAN, SHBG) showed bidirectional associations with T2D. Genetic analyses also suggested potential mechanistic pathways in T2D aetiology, including effects of RTBDN and TSPAN8 on T2D mediated through BMI and SHBG, respectively. ConclusionsWe identified multiple candidate proteins and biological pathways involved in T2D development, including novel protein clusters reflecting disease heterogeneity. These findings improve understanding of the molecular architecture of T2D and highlight potential biomarkers and therapeutic targets that may support precision prevention and treatment strategies. Research insightsO_ST_ABSWhat is currently known about this topic?C_ST_ABSO_LICurrent T2D therapies do not address disease heterogenous yielding different responses between patients. C_LIO_LIPlasma proteins offer opportunities to characterise T2D molecular biology. C_LI What is the key research question?O_LICan T2D-associated proteins be clustered by phenotypic protein - risk factor associations? C_LIO_LIAre proteins within these phenotype-derived clusters causally associated with T2D? C_LIO_LIHow do proteins link T2D through cluster-specific markers revealing the heterogeneous aetiology? C_LI What is new?O_LIFive protein clusters identified (Adiposity, Reduced-Adiposity, Lipids, Liver, Kidney); Reduced-Adiposity and Kidney clusters are novel. C_LIO_LI20 causal proteins identified (19 EUR, 4 EAS), with shared cross-ancestry signals. C_LI How might this study influence clinical practice?O_LIIdentifies protein drug targets for T2D and supports precision treatment via cluster mechanisms. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/25342701v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1187f5borg.highwire.dtl.DTLVardef@15155e1org.highwire.dtl.DTLVardef@dd421forg.highwire.dtl.DTLVardef@203a16_HPS_FORMAT_FIGEXP M_FIG C_FIG