Association Between Adrenergic Receptor Modulation And The Risk Of Heart Failure: A Two-Sample Mendelian Randomization Study

Introduction: The impact of the sympathetic nervous system (SNS) modulation on the risk of heart failure (HF) outside of ß1 receptor blockade remains controversial. Methods: We performed a two-sample Mendelian randomization (MR) study using common independent genetic variants located in the cis region of genes encoding the 9 SNS receptors (α1 A, B, D, α2 A, B, C and ß 1, 2 and 3) that were associated at genome-wide significance (P-value ≤ 5х10 –8 ) with blood pressure (BP) and/or heart rate (HR) in published genome-wide association studies (GWAS) available for BP and HR. Variants were filtered out by Linkage Disequilibrium clumping (LD R 2 > 0.1) and based on their minor allele frequency (MAF < 0.01). The effects of selected variants on the genetic risk of HF were extracted from a GWAS of HF from the HERMES consortium, based on a non-overlapping sample population. MR estimates were obtained using the Wald estimator for a single variant or the inverse variance weighted method for multiple variants. Results: 542,362 controls and 40,805 HF cases were evaluated. Independent variants in genes encoding 4 SNS receptors associated with BP or HR were identified as follows: α1A (diastolic BP), α2B (diastolic BP and HR), ß1 and ß2 (diastolic and systolic BP). MR analysis of α1A and ß1, weighted by their effects on diastolic BP, estimated an association with a higher risk of HF, while α2B variants were associated with a lower risk. We found no evidence for an effect of ß2. A similar relationship with systolic BP was found for ß1 and ß2. HR increasing effect of α2B variants was associated with a decreased odd of HF. Conclusions: Mindful of pleiotropic effects, these findings are consistent with the known benefits of ß1 blockade in HF and support a similar role for α1A blockade; conversely, they suggest a detrimental lowering effect of BP and HR through α2B modulation that deserves further studies. No evidence for a role of ß2 in HF was found.