Proteomic Predictors of Incident Diabetes: Results From the Atherosclerosis Risk in Communities (ARIC) Study
OBJECTIVE: The plasma proteome preceding diabetes can improve our understanding of diabetes pathogenesis. RESEARCH DESIGN AND METHODS: In 8,923 Atherosclerosis Risk in Communities (ARIC) Study participants (aged 47-70 years, 57% women, 19% Black), we conducted discovery and internal validation for associations of 4,955 plasma proteins with incident diabetes. We externally validated results in the Singapore Multi-Ethnic Cohort (MEC) nested case-control (624 case subjects, 1,214 control subjects). We used Cox regression to discover and validate protein associations and risk-prediction models (elastic net regression with cardiometabolic risk factors and proteins) for incident diabetes. We conducted a pathway analysis and examined causality using genetic instruments. RESULTS: There were 2,147 new diabetes cases over a median of 19 years. In the discovery sample (n = 6,010), 140 proteins were associated with incident diabetes after adjustment for 11 risk factors (P < 10-5). Internal validation (n = 2,913) showed 64 of the 140 proteins remained significant (P < 0.05/140). Of the 63 available proteins, 47 (75%) were validated in MEC. Novel associations with diabetes were found for 22 the 47 proteins. Prediction models (27 proteins selected by elastic net) developed in discovery had a C statistic of 0.731 in internal validation, with ΔC statistic of 0.011 (P = 0.04) beyond 13 risk factors, including fasting glucose and HbA1c. Inflammation and lipid metabolism pathways were overrepresented among the diabetes-associated proteins. Genetic instrument analyses suggested plasma SHBG, ATP1B2, and GSTA1 play causal roles in diabetes risk. CONCLUSIONS: We identified 47 plasma proteins predictive of incident diabetes, established causal effects for 3 proteins, and identified diabetes-associated inflammation and lipid pathways with potential implications for diagnosis and therapy.
Rooney, Mary R.; Chen, Jingsha; Echouffo-Tcheugui, Justin B.; Walker, Keenan A.; Schlosser, Pascal; Surapaneni, Aditya; Tang, Olive; Chen, Jinyu; Ballantyne, Christie M.; Boerwinkle, Eric; Ndumele, Chiadi E.; Demmer, Ryan T.; Pankow, James S.; Lutsey, Pamela L.; Wagenknecht, Lynne E.; Liang, Yujian; Sim, Xueling; van Dam, Rob; Tai, E Shyong; Grams, Morgan E.; Selvin, Elizabeth; and Coresh, Josef, "Proteomic Predictors of Incident Diabetes: Results From the Atherosclerosis Risk in Communities (ARIC) Study" (2023). GW Authored Works. Paper 2232.
Exercise and Nutrition Sciences