{"doi":"10.2337/dc22-1830","title":"Proteomic Predictors of Incident Diabetes: Results From the Atherosclerosis Risk in Communities (ARIC) Study","abstract":"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.","journal":"Diabetes Care","year":2023,"id":322349,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":40,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.6332,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":624479,"name":"Jingsha Chen","orcid":null,"position":1,"is_corresponding":false},{"id":377294,"name":"Justin B. Echouffo‐Tcheugui","orcid":"0000-0002-8460-1617","position":2,"is_corresponding":false},{"id":34922,"name":"Keenan A. Walker","orcid":"0000-0002-5989-9853","position":3,"is_corresponding":false},{"id":334102,"name":"Pascal Schlosser","orcid":"0000-0002-8460-0462","position":4,"is_corresponding":false},{"id":232664,"name":"Aditya Surapaneni","orcid":"0000-0003-4978-5980","position":5,"is_corresponding":false},{"id":333107,"name":"Olive Tang","orcid":null,"position":6,"is_corresponding":false},{"id":583412,"name":"Jinyu Chen","orcid":"0000-0002-7039-9091","position":7,"is_corresponding":false},{"id":233725,"name":"Christie M. Ballantyne","orcid":"0000-0002-6432-1730","position":8,"is_corresponding":false},{"id":245381,"name":"Eric Boerwinkle","orcid":"0000-0001-8813-0544","position":9,"is_corresponding":false},{"id":340495,"name":"Chiadi E. Ndumele","orcid":"0000-0002-1603-282X","position":10,"is_corresponding":false},{"id":36326,"name":"Ryan T. Demmer","orcid":"0000-0003-3429-0379","position":11,"is_corresponding":false},{"id":25001,"name":"James S. Pankow","orcid":"0000-0001-7076-483X","position":12,"is_corresponding":false},{"id":98923,"name":"Pamela L. Lutsey","orcid":"0000-0002-1572-1340","position":13,"is_corresponding":false},{"id":305437,"name":"Lynne E. Wagenknecht","orcid":"0000-0002-9980-0889","position":14,"is_corresponding":false},{"id":986222,"name":"Yujian Liang","orcid":null,"position":15,"is_corresponding":false},{"id":240625,"name":"Xueling Sim","orcid":"0000-0002-1233-7642","position":16,"is_corresponding":false},{"id":260010,"name":"Rob M. van Dam","orcid":"0000-0002-7354-8734","position":17,"is_corresponding":false},{"id":1122,"name":"E. Shyong Tai","orcid":"0000-0003-2929-8966","position":18,"is_corresponding":false},{"id":73169,"name":"Morgan E. Grams","orcid":"0000-0002-4430-6023","position":19,"is_corresponding":false},{"id":266269,"name":"Elizabeth Selvin","orcid":"0000-0001-6923-7151","position":20,"is_corresponding":false},{"id":23021,"name":"Josef Coresh","orcid":"0000-0002-4598-0669","position":21,"is_corresponding":false},{"id":441182,"name":"Mary R. Rooney","orcid":"0000-0002-5607-4848","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T01:07:42.497873Z","pmid":"36706097","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}