Association between beta-1-adrenoceptor blockade and risk of Raynaud's phenomenon: Mendelian randomisation study

Raynaud's phenomenon is a common vasospastic disorder associated with reduced health-related quality of life and, occasionally, ischaemic tissue damage depending on aetiology. The effect of beta-1-adrenoceptor blockers (e.g. bisoprolol, atenolol) on Raynaud's phenomenon remains unclear. We aimed to assess the association between genetically mimicked beta-1-adrenoceptor blockade and the risk of Raynaud's phenomenon.

We used two protein-coding single nucleotide polymorphisms in the ADRB1 gene, rs1801252 (A > G; Ser49Gly) and rs1801253 (G > C; Arg389Gly), to derive an unweighted allele count as the instrumental variable, using individual-level UK Biobank data. Raynaud's phenomenon was defined using International Classification of Diseases or Read codes. We used the ratio method and analysis was performed separately using systolic and diastolic blood pressure as the biomarker. To examine the validity of this approach and the Raynaud's phenomenon case definition, we also tested the known association between phosphodiesterase-5 inhibition and Raynaud's phenomenon risk.

Analysis included 4743 individuals with Raynaud's phenomenon (mean age 58 years, 68% female) and 403,762 controls. There was no evidence of an effect of genetically mimicked beta-1-adrenoreceptor blockade on the risk of Raynaud's phenomenon, using systolic blood pressure (odds ratio = 0.93 per mmHg reduction; 95% confidence interval = [0.83, 1.04]; p = 0.19) or diastolic blood pressure (odds ratio = 0.91 per mmHg reduction; 95% confidence interval = [0.78, 1.05]; p = 0.19). The positive control exposure phosphodiesterase-5 inhibition was associated with reduced Raynaud's phenomenon risk.

We found no genetic evidence to support a causal association between beta-1-adrenoceptor blockade and Raynaud's phenomenon risk in either direction. Randomised controlled trials are required to confirm the safety of beta-1-adrenoceptor blockers in people with Raynaud's phenomenon.