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We aimed to explore novel small metabolites that associated with hypertension risk in a population-based nested case-control study. Among 460 individuals with optimal blood pressure (<120/80 mmHg) at baseline, 55 progressed to hypertension during 5 years of follow-up. Twenty-nine cases of incident hypertension and 29 controls, matched for age, sex, and baseline systolic blood pressure, were included in this study. Serum metabolites were measured by gas chromatography-tandem mass spectrometry.  t -test and logistic regression analysis were applied to investigate the association between metabolites and incident hypertension. Among the 241 metabolites identified in this study, baseline levels of 26 metabolites were significantly different between hypertension and control groups. After adjusting for body mass index, smoking, and drinking, 16 out of the 26 metabolites were still associated with hypertension risk including four amino acids. Amino acids were negatively associated with risk of future hypertension, with odds ratio (OR) ranging from 0.33 to 0.53. Two of these amino acids were essential amino acids including threonine and phenylalanine. Higher level of lyxose, a fermentation product of gut microbes, was associated with higher risk of hypertension. Our study identified multiple metabolites that associated with hypertension risk. These findings implied that low amino acid levels and gut microbiome might play an important role in the pathogenesis of hypertension.

A Nested Case-Control Study of Association between Metabolome and Hypertension Risk