Abstract
To assess the use of plasma free amino acids (PFAAs) as biomarkers for metabolic disorders, it is essential to identify genetic factors that influence PFAA concentrations. PFAA concentrations were absolutely quantified by liquid chromatography–mass spectrometry using plasma samples from 1338 Japanese individuals, and genome-wide quantitative trait locus (QTL) analysis was performed for the concentrations of 21 PFAAs. We next conducted a conditional QTL analysis using the concentration of each PFAA adjusted by the other 20 PFAAs as covariates to elucidate genetic determinants that influence PFAA concentrations. We identified eight genes that showed a significant association with PFAA concentrations, of which two, SLC7A2 and PKD1L2, were identified. SLC7A2 was associated with the plasma levels of arginine and ornithine, and PKD1L2 with the level of glycine. The significant associations of these two genes were revealed in the conditional QTL analysis, but a significant association between serine and the CPS1 gene disappeared when glycine was used as a covariate. We demonstrated that conditional QTL analysis is useful for determining the metabolic pathways predominantly used for PFAA metabolism. Our findings will help elucidate the physiological roles of genetic components that control the metabolism of amino acids.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.5 R&D Planning Dept., Ajinomoto Co., Inc, Tokyo 104-8315, JapanCirculating metabolite concentrations in the body can serve as useful biomarkers for the diagnosis, prognosis, and risk assessment of diseases, for metabolic disorders such as diabetes, dyslipidemia, and hypertension [1,2,3,4,5,6,7,8]
There were no non-synonymous variants for the PSPH or PAH gene. We investigated whether these SNPs within the eight loci identified in the current study or those that were in strong linkage disequilibrium (LD) with them influenced gene expression using the Human Genetic Variation Database (HGVD) expression quantitative trait locus (QTL) information [22]
We conducted a QTL analysis of the absolute concentrations of plasma free amino acids (PFAAs) quantified by LC-MS technology
Summary
Circulating metabolite concentrations in the body can serve as useful biomarkers for the diagnosis, prognosis, and risk assessment of diseases, for metabolic disorders such as diabetes, dyslipidemia, and hypertension [1,2,3,4,5,6,7,8] Among these metabolites, the free amino acids in plasma (PFAAs) are key regulators of metabolic pathways, and their concentrations are influenced by both genetic and environmental factors, such as the diet [9,10,11,12,13,14]. Quantification was considered successful when the obtained value was within the determination range of the calibration curve
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