Proteomic Signatures of 3-Year Progression From Impaired Fasting Glucose to Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study
Mary R. Rooney, Justin B. Echouffo Tcheugui, Jingsha Chen, Keenan A. Walker, Christie M. Ballantyne, Eric Boerwinkle, Tanika N. Kelly, Chiadi E. Ndumele, James S. Pankow, Morgan E. Grams, Wendy S. Post, Peter J. Ganz, Alexis C. Wood, Jerome I. Rotter, Elizabeth Selvin, Josef CoreshOBJECTIVE
To identify proteomic signatures underlying 3-year progression from impaired fasting glucose (IFG) to diabetes.
RESEARCH DESIGN AND METHODS
We examined IFG progression in the Atherosclerosis Risk in Communities (ARIC) study from visit 2 (1990–1992) to visit 3 (1993–1995). We tested associations of 4,955 plasma proteins (SomaScan version 4.0) with ∼3-year progression from IFG (FG 100–125 mg/dL without diabetes) to diabetes (diagnosis, medication, or FG ≥126 mg/dL) using logistic regression models adjusted for demographics, cardiometabolic risk factors, and baseline glucose with Bonferroni correction (P < 10−5). We explored biological pathways enriched among the top proteins and calculated improvements in prediction (ΔAUC and net reclassification using 3-year risk thresholds of 6% and 15% in 80% training and 20% internal validation subsamples). We validated results in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.
RESULTS
There were 3,786 ARIC participants with IFG (mean [SD] age 57 [6] years, 52% female, 28% Black individuals). The 3-year cumulative incidence of diabetes was 6%. Six proteins were associated with ∼3-year progression to diabetes, namely lower receptor-type tyrosine-protein phosphatase S (PTPRS), anthrax toxin receptor 2 (ANTXR2), adiponectin (ADIPOQ), ciliary neurotrophic factor receptor subunit α (CNTFR), transmembrane protein 132C (TMEM132C), and higher ADAMTS-like protein 2 (ADAMTSL2). Altered carbohydrate metabolism and glycolysis were key pathways. Adding the six proteins to covariates improved discrimination (optimism-corrected AUC 0.81, ΔAUC 0.03, P = 0.005) and net reclassification (training 12.2%, internal validation 12.0%) with predicted diabetes risk quintiles spanning <1% to ∼20%. Two of the six proteins were validated in MESA (P < 0.008).
CONCLUSIONS
We identified proteins associated with 3-year IFG progression, with improvements in diabetes risk stratification.