Development of hypertension is influenced by genes, environmental effects, and their interactions, and the human metabolome is a measurable manifestation of gene-environment interaction. We explored the metabolomic antecedents of developing incident hypertension in a sample of blacks, a population with a high prevalence of hypertension and its comorbidities. We examined 896 black normotensives (565 women; aged, 45-64 years) from the Atherosclerosis Risk in Communities study, whose metabolome was measured in serum collected at the baseline examination and analyzed by high-throughput methods. The analyses presented here focus on 204 stably measured metabolites during a period of 4 to 6 weeks. Weibull parametric models considering interval censored data were used to assess the hazard ratio for incident hypertension. We used a modified Bonferroni correction accounting for the correlations among metabolites to define a threshold for statistical significance (P<3.9 × 10(-4)). During 10 years of follow-up, 38% of baseline normotensives developed hypertension (n=344). With adjustment for traditional risk factors and estimated glomerular filtration rate, each +1SD difference in baseline 4-hydroxyhippurate, a product of gut microbial fermentation, was associated with 17% higher risk of hypertension (P=2.5 × 10(-4)), which remained significant after adjusting for both baseline systolic and diastolic blood pressure (P=3.8 × 10(-4)). After principal component analyses, a sex steroids pattern was significantly associated with risk of incident hypertension (highest versus lowest quintile hazard ratio, 1.72; 95% confidence interval, 1.05-2.82; P for trend, 0.03), and stratified analyses suggested that this association was consistent in both sexes. Metabolomic analyses identify novel pathways in the pathogenesis of hypertension.
Keywords: blacks; hypertension; metabolomics; risk factors.