Proteomic Signatures of Adiposity in Middle-Aged Adults: The Atherosclerosis Risk in Communities (ARIC) Study

Background: Excess adiposity is linked to adverse cardiovascular outcomes via direct and indirect effects on metabolic pathways. There is limited large-scale data assessing proteomic signatures of adiposity. Methods: We quantified 4,955 plasma proteins using SomaLogic v4.0 in stored plasma samples of 9,940 ARIC Visit 2 participants (1990-92, mean age: 57±6 years, 55% women, 22% Black adults, 28% with obesity). We used linear regression and Bonferroni-corrected p-values to identify proteins associated with body mass index (BMI) in 2/3 discovery and 1/3 validation samples. We performed additional analyses to assess key pathways associated with obesity. Results: In the discovery sample (28% with obesity), after adjusting for age, sex, race-center, eGFR, 1,312 proteins were significantly associated with BMI. After further adjustments for clinical and lifestyle risk factors (Figure), 975 proteins were significantly associated with BMI (p<10 -5 ). There were 713 proteins confirmed in the validation sample (p<0.05/975). Among the confirmed proteins, there were >500 proteins that did not have previously described BMI associations in population studies (including serine protease HTRA1, seizure 6-like protein) as well as proteins with known BMI associations (including leptin, fatty acid binding proteins, insulin-like growth factor-binding proteins). Acute phase response, atherosclerosis signaling, hepatic fibrosis, pancreatic cancer and lipid metabolism were among the top biological pathways overrepresented by the proteins associated with BMI (Figure). The upstream regulators of these proteins included interleukins (IL-17A, IL-13, IL-4), as well as tumor necrosis factor (TNF), which was activated. Conclusion: We discovered several novel proteins associated with adiposity and confirmed previously identified proteins. Alteration in the plasma proteome related to adiposity is linked to differential regulation of inflammatory and metabolic pathways independent of cardiovascular risk mediators.