Metabolomic Architecture of Obesity Implicates Metabolonic Lactone Sulfate in Cardiometabolic Disease.

Abstract Objective Identify and characterize circulating metabolite profiles associated with adiposity to inform precision medicine. Methods Untargeted plasma metabolomic profiles in the Insulin Resistance Atherosclerosis Family Study (IRASFS) Mexican American cohort (n=1108) were analyzed for association with anthropometric (body mass index, BMI; waist circumference, WC; waist-to-hip ratio, WHR) and computed tomography measures (visceral adipose, VAT; subcutaneous adipose, SAT; visceral-to-subcutaneous ratio, VSR) of adiposity. Genetic data, inclusive of genome-wide array-based genotyping and whole exome (WES) and whole genome sequencing (WGS) were evaluated to identify genetic contributors. Phenotypic and genetic association signals were replicated across ancestries. Transcriptomic data was analyzed to explore the relationship between genetic and metabolomic data. Results A partially characterized metabolite, tentatively named metabolonic lactone sulfate (X-12063), was consistently associated with BMI, WC, WHR, VAT and SAT in IRASFS Mexican Americans (PMA 0.47) and a significant genetic signal at the ZSCAN25/CYP3A5 locus (PMA=9.00x10-41, PAA=2.31x10-10), highlighting a putative functional variant (rs776746, CYP3A5*3). Transcriptomic analysis in the African American Genetics of Metabolism and Expression (AAGMEx) cohort supported the association of CYP3A5 with metabolonic lactone sulfate levels (PFDR=6.64x10-07). Conclusions Variant rs776746 is associated with a decrease in transcript levels of CYP3A5 that is in turn associated with increased metabolonic lactone sulfate and poor cardiometabolic health.