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

Research output: Contribution to journalArticle

Abstract

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. .

Details

Authors
  • 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
  • Jonathan D Mosley
  • Steven A Carr
  • Ramachandran S Vasan
  • Martin G Larson
  • Thomas J Wang
  • Qiong Yang
  • Robert E Gerszten
Organisations
External organisations
  • Beth Israel Deaconess Medical Center
  • Boston University
  • Broad Institute
  • Stanford University
  • Skåne University Hospital
  • Sahlgrenska University Hospital
  • Vanderbilt University Medical Center
  • National Heart Lung and Blood Institute
  • University of Texas Southwestern Medical Center
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
JournalJCI Insight
Volume6
Issue number5
Early online date2021 Feb 16
Publication statusPublished - 2021
Publication categoryResearch
Peer-reviewedYes