Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study

Abstract

Background Observational studies have suggested a close but controversial relationship between blood pressure (BP) and amyotrophic lateral sclerosis (ALS). However, it remains unclear whether this association is causal. The authors employed a bidirectional two-sample Mendelian randomization (MR) approach to investigate whether there is a causal relationship between BP and ALS. Genetic proxies for systolic blood pressure (SBP), diastolic blood pressure (DBP), antihypertension drugs (AHDs), ALS, and their corresponding genome-wide association studies (GWAS) summary datasets were obtained from the updated largest studies. Inverse variance weighted (IVW) method was adopted as the main approach to examine the effect of BP on ALS and four other MR methods for sensitivity analyses. To exclude the interference between SBP and DBP, multivariable MR was used. Results We found that genetically determined increased DBP was a protective factor for ALS (OR = 0.978, 95% CI 0.960–0.996, P = 0.017), and increased SBP was an independent risk factor for ALS (OR = 1.014, 95% CI 1.003–1.025, P = 0.015). The high level of targeted protein of Calcium channel blocker (CCB) showed a causative relationship with ALS (OR = 0.985, 95% CI 0.971-1.000, P = 0.049). No evidence was revealed that ALS caused results change of BP measurements. Conclusions This study demonstrated that an increase in DBP is a protective factor for ALS, and increased SBP is independently risk for ALS, which may be related to sympathetic excitability. Blood pressure management is important in ALS, in which CCB may be a promising candidate.

Harnessing Transcriptomic Signals for Amyotrophic Lateral Sclerosis to Identify Novel Drugs and Enhance Risk Prediction

“…The most strongly enriched drug class predicted to have therapeutic benefits for ALS was selective calcium channel blockers, drugs primarily used to treat hypertension. Several studies show an association between hypertension and ALS, with a recent mendelian randomisation study supporting a causal role between prescription of calcium channel blockers and reduced risk of ALS (Xia et al, 2022), supporting the results of this study and highlighting a novel therapeutic avenue for ALS. In addition, we identified antiepileptic drugs were strongly enriched for interactions with ALS associated genes, however their direction of effect is predicted to exacerbate ALS risk.…”