Abstract 14024: Proteomic Predictors of Transitioning From Metabolically Healthy to Unhealthy Status in Middle-Aged Adults: The Atherosclerosis Risk in Communities (ARIC) Study

Abstract

Background: Metabolic health status predicts adverse cardiovascular outcomes. Among persons with similar weight, some metabolically healthy individuals stay metabolically healthy, whereas others develop metabolic syndrome (MetS) over time. Hypothesis: Plasma proteins can identify biological correlates of transitioning from metabolically healthy to unhealthy status. Methods: We quantified 4,955 plasma proteins using SomaLogic v4.0 in stored samples of ARIC Visit 2 participants. We assessed metabolic health at Visits 2 (1990-92) and 4 (1996-98). We split the sample into 2/3 discovery and 1/3 validation subsamples and used Bonferroni-corrected p-values. Among metabolically healthy individuals (no MetS) at Visit 2, we evaluated the associations of baseline plasma protein concentrations with the odds of developing metabolic unhealthy status by Visit 4 using logistic regression. We performed gene product enrichment analysis to assess biological pathways associated with transitioning to metabolically unhealthy status. Results: We included 4,539 participants (mean age: 56±6 years, 58% women, 17% Black adults, mean BMI 25 kg/m 2 ). Adjusting for confounders, 306 proteins were significantly associated with transitioning from metabolically healthy to unhealthy status. After further adjustment for BMI, 121 proteins had significant associations (p<10 -5 ). Of these, 49 proteins were validated (p<0.05/121). We identified proteins with known associations (growth hormone receptor, adiponectin, plasminogen activator inhibitor) with metabolically unhealthy status and ~20 novel proteins (MXRA8, VOPP1, CRYZL1). Biological pathways overrepresented by these proteins included tyrosine kinase signaling, complement and coagulation cascades, and calcium signaling pathways. Conclusions: Plasma proteins are linked to developing metabolic unhealthy status over 6 years. These proteins could be useful in identifying and preventing poor metabolic health.