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Olle Melander

Principal investigator

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Proteomic profiling reveals novel biomarkers and pathways in yype 2 diabetes risk

Author

  • Debby Ngo
  • Mark D Benson
  • Jonathan Z Long
  • Zsu-Zsu Chen
  • Ruiqi Wang
  • Anjali K Nath
  • Michelle J Keyes
  • Dongxiao Shen
  • Sumita Sinha
  • Eric Kuhn
  • Jordan E Morningstar
  • Xu Shi
  • Bennet D Peterson
  • Christopher Chan
  • Daniel H Katz
  • Usman A Tahir
  • Laurie A Farrell
  • Olle Melander
  • Jonathan D Mosley
  • Steven A Carr
  • Ramachandran S Vasan
  • Martin G Larson
  • J Gustav Smith
  • Thomas J Wang
  • Qiong Yang
  • Robert E Gerszten

Summary, in English

Recent advances in proteomic technologies have made high throughput profiling of low abundance proteins in large epidemiological cohorts increasingly feasible. We investigated whether aptamer-based proteomic profiling could identify biomarkers associated with future development of type 2 diabetes (T2DM) beyond known risk factors. We identified dozens of markers with highly significant associations with future T2DM across two large longitudinal cohorts (n=2,839) followed for up to 16 years. We leveraged proteomic, metabolomic, genetic and clinical data from humans to nominate one specific candidate to test for potential causal relationships in model systems. Our studies identified functional effects of aminoacylase 1 (ACY1), a top protein association with future T2DM risk, on amino acid metabolism and insulin homeostasis in vitro and in vivo. Further, a loss-of-function variant associated with circulating levels of the biomarker WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 2 (WFIKKN2) was in turn associated with fasting glucose, hemoglobin A1c and HOMA-IR measurements in humans. In addition to identifying novel disease markers and potential pathways in T2DM, we provide publicly available data to be leveraged for new insights about gene function and disease pathogenesis in the context of human metabolism. .

Department/s

  • EXODIAB: Excellence in Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health
  • Cardiovascular Research - Hypertension
  • WCMM-Wallenberg Centre for Molecular Medicine
  • Heart Failure and Mechanical Support
  • Cardiovascular Epigenetics
  • Cardiology
  • Molecular Epidemiology and Cardiology

Publishing year

2021-02-16

Language

English

Publication/Series

JCI Insight

Volume

6

Issue

5

Document type

Journal article

Publisher

The American Society for Clinical Investigation

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Cardiovascular Research - Hypertension
  • Heart Failure and Mechanical Support
  • Cardiovascular Epigenetics
  • Molecular Epidemiology and Cardiology

ISBN/ISSN/Other

  • ISSN: 2379-3708