Genetically proxied tocilizumab (IL6R inhibition) was associated with a significantly reduced risk of aortic stenosis (OR 0.56), supporting an inflammatory hypothesis of pathogenesis.
Observational (n=653,867)
Yes
Does genetically proxied immunomodulation (tocilizumab, canakinumab, colchicine) reduce the risk of aortic stenosis in European populations?
Genetically proxied IL6R inhibition is associated with a reduced risk of aortic stenosis, supporting an inflammatory hypothesis of pathogenesis and identifying a potential therapeutic target.
Effect estimate: OR 0.56 (95% CI 0.45-0.70)
There are currently no approved pharmacological treatment options for aortic stenosis (AS), and there are limited identified drug targets for this chronic condition. It remains unclear whether inflammation plays a role in AS pathogenesis and whether immunomodulation could become a therapeutic target. We evaluated the potentially causal association between inflammation and AS by investigating the genetically proxied effects of tocilizumab (IL6 receptor, IL6R, inhibitor), canakinumab (IL1β inhibitor) and colchicine (β-tubulin inhibitor) through a Mendelian randomisation (MR) approach. Genetic proxies for these drugs were identified as single nucleotide polymorphisms (SNPs) in the gene, enhancer or promoter regions of IL6R, IL1β or β-tubulin gene isoforms, respectively, that were significantly associated with serum C-reactive protein (CRP) in a large European genome-wide association study (GWAS; 575,531 participants). These were paired with summary statistics from a large GWAS of AS in European patients (653,867 participants) to then perform primary inverse-variance weighted random effect and sensitivity MR analyses for each exposure. This analysis showed that genetically proxied tocilizumab was associated with reduced risk of AS (OR 0.56, 95% CI 0.45-0.70 per unit decrease in genetically predicted log-transformed CRP). Genetically proxied canakinumab was not associated with risk of AS (OR 0.80, 95% CI 0.51-1.26), and only one suitable SNP was identified to proxy the effect of colchicine (OR 34.37, 95% CI 1.99-592.89). The finding that genetically proxied tocilizumab was associated with reduced risk of AS is concordant with an inflammatory hypothesis of AS pathogenesis. Inhibition of IL6R may be a promising therapeutic target for AS management.
Ciofani et al. (Wed,) conducted a observational in Aortic stenosis (n=653,867). Genetically proxied tocilizumab (IL6R inhibitor) vs. Genetically predicted higher CRP (control) was evaluated on Risk of aortic stenosis (OR 0.56, 95% CI 0.45-0.70). Genetically proxied tocilizumab (IL6R inhibition) was associated with a significantly reduced risk of aortic stenosis (OR 0.56), supporting an inflammatory hypothesis of pathogenesis.