Proteomic Signature of Body Mass Index and Risk of Type 2 Diabetes

The obesity diagnosis by body mass index (BMI) exhibits considerable interindividual heterogeneity in metabolic phenotypes and risk of developing type 2 diabetes (T2D). We investigated the association of proteomic signature of BMI and T2D and examined whether the proteomic signature of BMI improves prediction of T2D risk. This study included 41,427 adults in the UK Biobank who were free of T2D at baseline and had complete data on proteomics metrics assessed by antibody based Olink assay. The main exposure was a proteomic BMI score (pro-BMI score) calculated from 67 pre-identified plasma proteins associated with BMI. During a median follow-up of 13.7 years, 2,030 incident events of T2D were documented. We observed that a higher proteomic BMI (pro-BMI) score was significantly associated with a higher risk of T2D independent of actual BMI, waist-to-hip ratio, and polygenic risk score for BMI (hazard ratio (HR) comparing the highest with the lowest quartiles was 3.81, 95% CI, 3.08 – 4.71). Pro-BMI score significantly increased the C index when added to a reference model with age, sex, and BMI (C index change, 0.023 [95%CI, 0.018 to 0.027]). Proteomic signature of BMI is significantly associated with the risk of T2D independent of BMI, WHR and genetic susceptibility to obesity. When added to actual BMI, the proteomic signature of BMI provides significant but modest improvement in discrimination.