Influence of Genetic West African Ancestry on Metabolomics among Hypertensive Patients

Abstract

Patients with higher genetic West African ancestry (GWAA) have hypertension (HTN) that is more difficult to treat and have higher rates of cardiovascular diseases (CVD) and differential responses to antihypertensive drugs than those with lower GWAA. The mechanisms underlying these disparities are poorly understood. Using data from 84 ancestry-informative markers in US participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, the GWAA proportion was estimated. Using multivariable linear regression, the baseline levels of 886 metabolites were compared between PEAR participants with GWAA < 45% and those with GWAA ≥ 45% to identify differential metabolites and metabolic clusters. Metabolites with a false discovery rate (FDR) < 0.2 were used to create metabolic clusters, and a cluster analysis was conducted. Differential clusters were then tested for replication in PEAR-2 participants. We identified 353 differential metabolites (FDR < 0.2) between PEAR participants with GWAA < 45% (n = 383) and those with GWAA ≥ 45% (n = 250), which were used to create 24 metabolic clusters. Of those, 13 were significantly different between groups (Bonferroni p < 0.002). Four clusters, plasmalogen and lysoplasmalogen, sphingolipid metabolism and ceramide, cofactors and vitamins, and the urea cycle, were replicated in PEAR-2 (Bonferroni p < 0.0038) and have been previously linked to HTN and CVD. Our findings may give insights into the mechanisms underlying HTN racial disparities.