D. Rotroff,1 L. Yerges-Armstrong,2 J. Lewis,2 A. Beitleshees,2 R. Horenstein,2 A. Shuldiner,2 A. Motsinger-Reif,1 R. Kaddurah-Daouk3; 1North Carolina State University, Raleigh, NC, 2University of Maryland School of Medicine, Baltimore, MD, 3Duke University Medical Center, Durham, NC
BACKGROUND: Serum metabolite levels provide critical information in elucidating mechanisms of complex physiological processes. The field of pharmacometabolomics has shown great promise to identify biomarkers that can predict disease progression and better inform treatment outcomes. However, little is known about the genetic determinants and heritability of metabolite levels. Increased understanding of genetic and environmental contributions to metabolite levels may help us better characterize disease etiology and response variability.
METHODS: We measured 42 amine metabolites in 198 Amish subjects from the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study. These subjects were genotyped using an exome chip. Given the detailed pedigree data available in this cohort, we were positioned to estimate the heritablility (H2) of circulating amine metabolites. H2 was estimated and genome wide associations with baseline metabolites were determined.
RESULTS: Several metabolites were identified with high baseline H2 estimates. Glycine, L-proline, o-acetyl-L-serine, L-glutamic acid, and serotonin had H2 > 0.7 (p < .01). Several genetic variants were highly associated with baseline metabolite levels suggesting a potential role for drug metabolizing enzymes (p < 1x10-8). In addition, we estimated the overall genetic and environmental contribution to baseline amine levels.
CONCLUSION: This analysis provides insight into the genetic contribution of amine metabolite levels and identifies key metabolizing enzymes that may play an important role in response to antiplatelet therapies. Furthermore, this approach highlights novel aspects of genomics and metabolomics that may improve prediction of treatment outcomes.