Objective  To investigate the association and causal relationship between plasma metabolites and salt sensitive hypertension (SSH) using association analysis and Mendelian randomization (MR).

Methods  Based on the baseline survey data from the System Epidemiology Study on Salt Sensitivity of Blood Pressure (EpiSS), 60 participants were selected for untargeted metabolomics and whole-genome genotyping. Multivariable Logistic regression analysis was conducted to explore the association between plasma metabolites and SSH. One-sample and two-sample MR analyses and sensitivity analysis were performed to assess the causal relationship between metabolites and SSH.

Results  A total of 970 metabolites were measured, 73 of which showed a statistically significant association with SSH (P<0.05). After false discovery rate (FDR) correction, ceramide Cer (d34:0) and Cer (d40:1) remained significantly positively associated with SSH, with OR (95%CI) of 1.55 (1.36, 1.76) and 2.19 (1.66, 2.91), respectively. The one-sample MR analysis revealed a causal relationship between Cer (d40:1) and SSH, with both simple genetic risk score (GRS) [OR=2.470, 95%CI (1.887, 3.234)] and weighted GRS [OR=3.362, 95%CI (1.303, 8.674)]. Two-sample MR analysis did not find a causal relationship between Cer (d34:0) and Cer (d40:1) and SSH (P>0.05).

Conclusion  This study identified plasma metabolites Cer (d34:0) and Cer (d40:1) as potential risk factors for SSH, with MR results further supporting a causal relationship between Cer (d40:1) and SSH. These findings provide new evidence for early screening and etiological research of SSH.

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