Abstract MP74: The Effect Of BMI On Metabolic Traits Is Mediated By A Novel Diabetes Marker

Introduction: 2-aminoadipic acid (2-AAA) secreted during adipogenesis is a novel marker for diabetes. Hypothesis: 2-AAA mediates the associations between body mass index (BMI) and metabolic measures, and the effect of 2-AAA can be modified by environmental factors. Methods: We performed cross-sectional analyses among all 1,252 participants in the Bogalusa Heart Study 2016 survey. Serum 2-AAA and 110 xenobiotics were profiled through untargeted UPLC-MS/MS. Mediation effects of 2-AAA on the associations between BMI and metabolic traits were estimated by comparing the BMI-traits associations before and after controlling for 2-AAA. P value for a mediation effect was estimated by 1,000,000 times Monte-Carlo simulation. We further performed interaction analyses to identify xenobiotics that modify the effect of 2-AAA on metabolic traits. Age, sex, race, education, smoking, drinking, and use of lipid, glucose, or blood pressure lowering medications were adjusted in all analyses. Results: After Bonferroni correction, 2-AAA significantly mediated the association of BMI with high density lipoprotein cholesterol (HDLC) (beta= -0.03 mg/dL, p=1.70х10 -4 ), log transformed triglyceride (lgTG) (beta=0.002, p=1х10 -6 ), fasting glucose (beta=0.05 mg/dL, p=2.87х10 -3 ), and hemoglobin A1c (HbA1c) (beta=0.002%, p=8.50х10 -4 ). The proportions of associations explained by 2-AAA ranged from 5.12% for HDLC to 13.23% for lgTG. When stratified by race and medication usage, the mediation effects were stronger among Whites and those not taking medications (P for interaction <0.05). Furthermore, 14 xenobiotics modified the associations of 2-AAA with HDLC/lgTG or glucose/HbA1c (Table), e.g., the association between 2-AAA and HbA1c was much stronger among participants with higher levels of 4-acetaminophen sulfate (P for interaction=3.03х10 -5 ), a metabolite of commonly used over-the-counter analgesics. Conclusion: 2-AAA mediated the effect of BMI on metabolic traits, and this effect was modified by environmental factors.