Abstract
Introduction and objectives
NOS1AP variant rs12742393 is a functional single nucleotide polymorphism (SNP) and has been reported to be associated with schizophrenia and type 2 diabetes (T2DM) susceptibility in different populations. However, the molecular mechanisms are not clear. The main focus of the present study was to identify metabolic differences among different genotypes of the variant and to identify potential physiological and pathological mechanisms for the diseases.
Methods
In this study, we conducted a comprehensive serum metabolomic analysis in healthy subjects with different genotypes of rs12742393 (n = 49 for AA, AC, and CC, respectively) using gas chromatography–time of flight mass spectrometry and ultra-performance liquid chromatography–quadruple time of flight mass spectrometry. Serotonin was also measured by enzyme-linked immunosorbent assay.
Results
Our data showed that there were significant metabolic differences among the different genotypes of rs12742393: compared with AA carriers, serum serotonin and N-acetyl-5-hydroxytryptamine were significantly higher; while tryptophan and kynurenine were significantly lower in CC allele carriers (variable importance in the projection (VIP) >1 and P < 0.05). In addition, CC allele carriers showed low levels of aromatic amino acids (phenylalanine and tyrosine) and fatty acids (lauric acid, 2-methyl-4-pentenoic acid, and adrenic acid), but a high level of isolithocholic acid (VIP >1 and P < 0.05).
Conclusion
The influence of rs12742393 variant is involved in a set of complex metabolic alterations, including amino acids, fatty acids and cholic acids, especially those in the serotonin and kynurenine pathway, probably associates with the early development of schizophrenia and T2DM.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Barradas, M. A., Gill, D. S., Fonseca, V. A., Mikhailidis, D. P., & Dandona, P. (1988). Intraplatelet serotonin in patients with diabetes mellitus and peripheral vascular disease. European Journal of Clinical Investigation, 18, 399–404.
Berger, M., Gray, J. A., & Roth, B. L. (2009). The expanded biology of serotonin. Annual Review of Medicine, 60, 355–366. doi:10.1146/annurev.med.60.042307.110802.
Brandacher, G., et al. (2006). Bariatric surgery cannot prevent tryptophan depletion due to chronic immune activation in morbidly obese patients. Obesity Surgery: The Official Journal of the American Society for Bariatric Surgery and of the Obesity Surgery Society of Australia and New Zealand, 16, 541–548. doi:10.1381/096089206776945066.
Capuron, L., et al. (2011). Chronic low-grade inflammation in elderly persons is associated with altered tryptophan and tyrosine metabolism: Role in neuropsychiatric symptoms. Biological Psychiatry, 70, 175–182. doi:10.1016/j.biopsych.2010.12.006.
Coyle, J. T., Tsai, G., & Goff, D. (2003). Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Annals of the New York Academy of Sciences, 1003, 318–327.
Erjavec, I., et al. (2016). Constitutively elevated blood serotonin is associated with bone loss and type 2 diabetes in rats. PLoS ONE, 11, e0150102. doi:10.1371/journal.pone.0150102.
Fukushima, T., et al. (2014). Quantitative analyses of schizophrenia-associated metabolites in serum: Serum D-lactate levels are negatively correlated with gamma-glutamylcysteine in medicated schizophrenia patients. PLoS ONE, 9, e101652. doi:10.1371/journal.pone.0101652.
Gershon, M. D., & Tack, J. (2007). The serotonin signaling system: From basic understanding to drug development for functional GI disorders. Gastroenterology, 132, 397–414. doi:10.1053/j.gastro.2006.11.002.
Hu, C., et al. (2010). Association of genetic variants of NOS1AP with type 2 diabetes in a Chinese population. Diabetologia, 53, 290–298. doi:10.1007/s00125-009-1594-2.
Huot, P., & Fox, S. H. (2013). The serotonergic system in motor and non-motor manifestations of Parkinson’s disease. Experimental brain research. Experimentelle Hirnforschung. Experimentation cerebrale, 230, 463–476. doi:10.1007/s00221-013-3621-2.
Jacobsen, J. P., Medvedev, I. O., & Caron, M. G. (2012). The 5-HT deficiency theory of depression: Perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin mouse. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 367, 2444–2459. doi:10.1098/rstb.2012.0109.
Jaffrey, S. R., Snowman, A. M., Eliasson, M. J., Cohen, N. A., & Snyder, S. H. (1998). CAPON: A protein associated with neuronal nitric oxide synthase that regulates its interactions with PSD95. Neuron, 20, 115–124.
Jansson, J., et al. (2009). Metabolomics reveals metabolic biomarkers of Crohn’s disease. PLoS ONE, 4, e6386. doi:10.1371/journal.pone.0006386.
Lajoix, A. D., et al. (2001). A neuronal isoform of nitric oxide synthase expressed in pancreatic beta-cells controls insulin secretion. Diabetes, 50, 1311–1323.
Lu, Y., et al. (2016). Metabolic signatures and risk of type 2 diabetes in a Chinese population: An untargeted metabolomics study using both LC-MS and GC-MS. Diabetologia, 59, 2349–2359. doi:10.1007/s00125-016-4069-2.
Mangge, H., Stelzer, I., Reininghaus, E. Z., Weghuber, D., Postolache, T. T., & Fuchs, D. (2014). Disturbed tryptophan metabolism in cardiovascular disease. Current Medicinal Chemistry, 21, 1931–1937.
Nicholson, J. K., Lindon, J. C., & Holmes, E. (1999). ‘Metabonomics’: Understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica; The Fate of Foreign Compounds In Biological Systems, 29, 1181–1189. doi:10.1080/004982599238047.
Qiu, Y., et al. (2009). Serum metabolite profiling of human colorectal cancer using GC-TOFMS and UPLC-QTOFMS. Journal of Proteome Research, 8, 4844–4850. doi:10.1021/pr9004162.
Rodriguez, J. J., Noristani, H. N., & Verkhratsky, A. (2012). The serotonergic system in ageing and Alzheimer’s disease. Progress in Neurobiology, 99, 15–41. doi:10.1016/j.pneurobio.2012.06.010.
Schefold, J. C., et al. (2009). Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: A possible link between chronic inflammation and uraemic symptoms. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association—European Renal Association, 24, 1901–1908. doi:10.1093/ndt/gfn739.
Wang, C., et al. (2014). Prevalence of type 2 diabetes among high-risk adults in Shanghai from 2002 to 2012. PLoS ONE, 9, e102926. doi:10.1371/journal.pone.0102926.
Wang, T. J., et al. (2011). Metabolite profiles and the risk of developing diabetes. Natural Medicines, 17, 448–453. doi:10.1038/nm.2307.
Weng, R., et al. (2015). Metabolomics approach reveals integrated metabolic network associated with serotonin deficiency. Scientific Reports, 5, 11864. doi:10.1038/srep11864.
Wratten, N. S., et al. (2009). Identification of a schizophrenia-associated functional noncoding variant in NOS1AP. The American Journal of Psychiatry, 166, 434–441. doi:10.1176/appi.ajp.2008.08081266.
Yang, J., et al. (2013). Potential metabolite markers of schizophrenia. Molecular Psychiatry, 18, 67–78. doi:10.1038/mp.2011.131.
Yokoi, N., et al. (2015). Identification of putative biomarkers for prediabetes by metabolome analysis of rat models of type 2 diabetes. Metabolomics, 11, 1277–1286. doi:10.1007/s11306-015-0784-9.
Zheng, H., Bidasee, K. R., Mayhan, W. G., & Patel, K. P. (2007). Lack of central nitric oxide triggers erectile dysfunction in diabetes. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 292, R1158–R1164. doi:10.1152/ajpregu.00429.2006.
Acknowledgements
This work was funded by grants from National Natural Science Foundation of China (Grant No. 81570808), The Innovation Foundation of Translational Medicine of Shanghai Jiao Tong University School of Medicine—Project of Precision Medicine (Grant No. 15ZH4006), Shanghai major clinical disease clinical sample pool of professional and technical services platform (Grant No. 15DZ2292100), the Global Science Alliance Program of Thermo-Fisher Scientific. We thank The Metabolic Diseases Biobank, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital and GSA program by Thermo.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declared that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Rights and permissions
About this article
Cite this article
Zhang, Y., Zhao, A., Hu, C. et al. Metabolomics reveals alterations of serotonin pathway in carriers of NOS1AP variant rs12742393. Metabolomics 13, 84 (2017). https://doi.org/10.1007/s11306-017-1221-z
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11306-017-1221-z