Causal Inference of Carnitine on Blood Pressure and potential mediation by uric acid: A mendelian randomization analysis

Background: Dietary change alters blood pressure (BP) but the specific causal dietary elements are unclear. Given previous observational data suggesting serum carnitine or uric acid affect BP, we investigated the role of serum carnitine and serum uric acid concentrations on BP, and considered mediation by lipids and insulin resistance using two-sample bi-directional Mendelian randomization (MR) analysis. Methods: We performed MR to characterize bi-directional causal relationships of carnitine or uric acid on cardiometabolic traits. We performed two-sample MR using genome-wide association summary data from separate large-scale genomic analyses of carnitine, uric acid, BP, lipids, and glycemic traits. We used inverse variance weighted (IVW) meta-analysis and MR Egger regression to test for causal relations in the absence and presence of pleiotropy, respectively, and performed sensitivity analyses to identify confounders and intermediates. Results: In our analysis, carnitine was directly, causally associated with systolic BP (IVW effect = 0.2, causal p-value = 0.03) but not diastolic BP (IVW causal p = 0.1). Our findings additionally support direct and indirect relationships of carnitine on TG and on uric acid. No causal associations of carnitine were found with glycemic traits. Uric acid was not associated with BP, nor TG. Conclusion: Two-sample bi-directional MR demonstrated an unconfounded causal effect of carnitine, but not uric acid, on systolic but not diastolic BP, suggesting a role of carnitine in arterial stiffness. Carnitine, but not uric acid, also has direct and indirect effects on TG but are independent of the causal effect of carnitine on systolic BP.