Finding the Biologically Important Exposures in the Exposome Through Circulating Antigen-antibody Complexes

摘要

Background Finding the causes of chronic diseases is one of the key goals in public health. It is known that only a small fraction of chronic disease variability is ascribed to inherited factors. Consequently, many are turning their attentions to the exposome concept to enable discovery of exposures in the post genome-wide association study era. However, the exposure spectrum is so large and complex that many exposures remain unknown. Objective We proposed a novel, high risk yet high reward, receptor-based approach to this challenge. Specifically, we hypothesized that daily bioactive chemical exposures that may influence health and disease could be discovered by studying the circulating immune complexes (CICs). Methods In this proof-of-concept study, we developed a method that coupled an immunoprecipitation technique with a high-resolution metabolomics platform to query the CIC extracts for unknown exposures. Peak alignment, identification, and annotation were done with XCMS. Then, to demonstrate the real-world values, we tested the method with a blood sample from a healthy adult volunteer with only environmental level of exposures. Results For the top 20 features, half of them were assigned with a putative identity. These included 5 drugs (Remikiren, Loperamide, Quinidine Barbiturate, Fexofenadine, & Metergelone), a natural product from fruit (1,5-dibutylmethylhydroxycitrate), a tripeptide (Gln-Lys-His), and a likely microbial metabolite (all-trans-hexaprenyl diphosphate). Although individual identities were not experimentally confirmed, the results collectively pointed to an exogenous origin of the extracted molecules that is in line with our hypothesis. Conclusions: The methodology of our biology-driven approach is sound, and robust and sensitive enough to recover trace molecules from CICs. This revolutionary approach could open the possibility to investigate a series of hypotheses in exposomics and ultimately drive a new generation of exposome-wide association study.