Oral Presentation HUPO 2019 - 18th Human Proteome Organization World Congress

Integrative analysis of plasma proteomes from prediabetes and diabetes progression: An IMI DIRECT study (#160)

Mun-Gwan Hong 1 , Ana Viñuela 2 , Ragna Häussler 1 , Matilda Dale 1 , Robert Koivula 3 , Anubha Mahajan 3 , Juan Fernandez 3 , Frederico De Masi 4 , Roberto Bizzotto 5 , Tim McDonald 6 , Petra Musholt 7 , Andrea Mari 5 , Imre Pavo 8 , Tarja Kokkola 9 , Oluf Borbye Pedersen 10 , Jurek Adamski 11 , Mark Walker 12 , Emmanouil Dermitzakis 2 , Søren Brunak 4 , Paul Franks 13 , Mark McCarthy 3 , Hartmut Ruetten 7 , Ewan Pearson 14 , Jochen M Schwenk 1
  1. SciLifeLab, KTH Royal Institute of Technology, Stockholm, Sweden
  2. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
  3. Oxford Centre for Diabetes Endocrinology and Metabolism, Oxford University, Oxford, UK
  4. Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
  5. Institute of Neuroscience, National Research Council, Padova, Italy
  6. Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
  7. Diabetes Division, Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany
  8. Eli Lilly, Vienna, Austria
  9. Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finnland
  10. The Novo Nordisk Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
  11. German Center for Diabetes Research (DZD), Munich, Germany
  12. Institute of Cellular Medicine, Newcastle University, Newcastle, UK
  13. Department of Clinical Science, Lund University, Malmö, Sweden
  14. Molecular and Clinical Medicine, University of Dundee, Dundee, Scotland

In-depth profiling of proteins in plasma can provide valuable insights on the complex processes related to metabolic diseases such as type 2 diabetes (T2D). Within the framework of the EU IMI project DIRECT (www.direct-diabetes.org) a multi-center cohort was built on 3100 subjects of which 2300 were at risk of developing of developing T2D (HbA1c~ 5.6 - 6.5%) as well as 800 with early T2D (HbA1c> 6.5%) [1].

We used several multiplexed affinity proteomic assays to profile ~600 unique proteins in EDTA plasma collected from 3100 study participants at baseline and 2500 at the 3 years (early T2D) or 4 years (risk for T2D) follow-up. With access to extensive metadata, our initial analysis focused on possible sample-related confounders. This identified several pre-analytical variables and consequently, we applied a linear mixed model that included age, sex, study center and sample collection date for defining proteins associated with any of the >50 quantitative clinical traits.

At baseline, we found > 300 proteins in plasma that were associated with diabetes related traits (adjusted p-value < 0.0001), many of which were prominently associated with BMI, such as leptin. Further, IGFBP1 and IGFBP2 associated 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 liver AST. Making use of other omics data, 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, which illustrated that many of the studied protein profiles are affected by a genetic component.

Our integrative, large-scale multi-omics analysis revealed insights about known and novel plasma proteins associated to pre- and early T2D, as well as indicators of progression and treatment response.

  1. Koivula RW, et al. Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: an overview of the data from the epidemiological studies within the IMI DIRECT Consortium. bioRxiv 300244; doi: https://doi.org/10.1101/300244