@article{9a368447d37b49ebb43f08174de3e40b,
title = "Proteomic profiling reveals biomarkers and pathways in type 2 diabetes risk",
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 2 large longitudinal cohorts (n = 2839) followed for up to 16 years. We leveraged proteomic, metabolomic, genetic, and clinical data from humans to nominate 1 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. Furthermore, 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 potentially novel disease markers and pathways in T2DM, we provide publicly available data to be leveraged for insights about gene function and disease pathogenesis in the context of human metabolism.",
author = "Debby Ngo and Benson, {Mark D.} and Long, {Jonathan Z.} and Chen, {Zsu Zsu} and Ruiqi Wang and Nath, {Anjali K.} and Keyes, {Michelle J.} and Dongxiao Shen and Sumita Sinha and Eric Kuhn and Morningstar, {Jordan E.} and Xu Shi and Peterson, {Bennet D.} and Christopher Chan and Katz, {Daniel H.} and Tahir, {Usman A.} and Farrell, {Laurie A.} and Olle Melander and Mosley, {Jonathan D.} and Carr, {Steven A.} and Vasan, {Ramachandran S.} and Larson, {Martin G.} and {Gustav Smith}, J. and Wang, {Thomas J.} and Qiong Yang and Gerszten, {Robert E.}",
note = "Funding Information: This work was supported by R01HL132320 to TJW, RSV, and REG; R01HL133870 to REG; R01DK081572 to REG and TJW; K01GM103817 to DN; and K08HL145095 to MDB. The FHS acknowledges the support of contracts NO1-HC-25195, HHSN268201500001I, and 75N92019D00031 from the National Heart, Lung, and Blood Institute. RSV is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. JGS and analyses in the MDCS were supported by grants from the Swedish Heart-Lung Foundation (2016-0134 and 2016-0315), the Swedish Research Council (2017-02554), the European Research Council (ERCSTG-2015-679242), the Cra-foord Foundation, Sk{\aa}ne University Hospital, the Scania county, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15-0067) to the Lund University Diabetes Center. This work was supported in part by a grant from the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium NIH/ NCI U24-CA210986 to SAC. This work was also supported in part by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases NIDDK 124265 to JZL. We acknowledge the dedication of the FHS and MDCS study participants, without whom this research would not be possible. Publisher Copyright: Copyright: {\textcopyright} 2021, Ngo et al.",
year = "2021",
month = mar,
day = "8",
doi = "10.1172/jci.insight.144392",
language = "English (US)",
volume = "6",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "5",
}