189-OR: Plasma Proteome Profiling of Prediabetes and Diabetes Progression: An IMI Direct Study

Abstract

Plasma proteins can provide valuable insights on human health and disease states. Within the framework of the EU IMI project DIRECT (https://www.direct-diabetes.org), we used a set of affinity proteomic methods to profile > 3100 study participants at baseline. Multiplexed assays quantified more than 600 unique proteins in EDTA plasma from this multi-center cohort that included 2300 subjects at risk of developing T2D (HbA1c ~ 6-6.5%) as well as 800 with early T2D (HbA1c > 6.5%). Using extensive clinical and other omics metadata available, the aim of the investigation was to identify plasma proteins associated with baseline traits. An initial analysis highlighted the importance of considering sample-related and pre-analytical variables as possible confounders in the data analysis. Hence, we used linear mixed models that included several parameters such as age, sex, study center and collection date. Next, we defined proteins associating with any of the >50 quantitative clinical traits at baseline. We found more than 300 proteins in plasma that were associated with diabetes related traits (adjusted p-value < 0.0001), many of which were prominently associated with BMI. The shortlisted candidates included leptin which associates with waist circumference and BMI; IGFBP1 and IGFBP2 to Matsuda; adiponectin to basal insulin secretion rate and fasting HDL; LDL receptor proteins to fasting triglycerides; APOM to fasting cholesterol; or IL8 and MCP-1 to fasting AST. In addition, we performed pQTL analysis to assess any connection between the protein values in plasma and genetic variants. We observed >400 cis-pQTLs (q-value < 0.05), such as for APOM (rs2736163, p = 5.15 e-24), which illustrated that many of the studied protein profiles are affected by a genetic component. With follow-up samples collected 3-4 years after starting the study, the baseline values will serve as valuable indicators of progression and allow study of how each participant's disease phenotype changes over time or due to treatment. Disclosure M. Hong: None. A. Viñuela: None. R.S. Häussler: None. M. Dale: None. R.W. Koivula: None. J. Fernandez-Tajes: None. A. Mahajan: None. R. Bizzotto: Research Support; Self; GlaxoSmithKline plc. A. Mari: Consultant; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim International GmbH. E. Dermitzakis: Advisory Panel; Self; DNAnexus LTD. Board Member; Self; Hybridstat LTD. M. McCarthy: Advisory Panel; Self; European Association for the Study of Diabetes, Pfizer Inc. Consultant; Self; Eli Lilly and Company, Merck & Co., Inc. Consultant; Spouse/Partner; Merck & Co., Inc. Research Support; Self; AbbVie Inc., Boehringer Ingelheim International GmbH. Research Support; Spouse/Partner; Diabetes UK. Research Support; Self; Janssen Pharmaceuticals, Inc., Merck & Co., Inc., National Institutes of Health. Research Support; Spouse/Partner; National Institutes of Health. Research Support; Self; Novo Nordisk A/S. Research Support; Spouse/Partner; Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation, Roche Pharma, Sanofi-Aventis, Servier, Takeda Pharmaceutical Company Limited. P.W. Franks: Board Member; Self; Zoe Ltd. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Novo Nordisk Foundation, Sanofi, Servier. E. Pearson: None. J.M. Schwenk: None. Funding Innovative Medicines Initiative Joint Undertaking (115317)