Interleukin-1 receptor antagonist, interleukin-2 receptor alpha subunit and amyotrophic lateral sclerosis

Background and purpose: To clarify the causal associations of interleukin-1 receptor antagonist (IL-1ra) and interleukin-2 receptor alpha subunit (IL-2r alpha) with the risk of amyotrophic lateral sclerosis (ALS). Methods: A two-sample Mendelian randomization study design was employed. Single-nucleotide polymorphisms associated with IL-1ra (n = 2) and IL-2r alpha (n = 1) at the genome-wide significance level were used as unbiased instrumental variables. Summary-level data for ALS were obtained from Project MinE, an international collaboration consortium with 12 577 ALS cases and 23 475 controls of European descent. Results: Genetic predisposition to higher levels of IL-1ra was significantly associated with lower odds of ALS. For a 1-SD increase of circulating IL-1ra levels, the odds ratio of ALS was 0.64 (95% confidence intervals, 0.46-0.88;P = 0.005). There was a borderline inverse association between IL-2r alpha levels and ALS (odds ratio, 0.91; 95% confidence intervals, 0.83-1.00;P = 0.058). Conclusions: Interleukin-1 receptor antagonist levels were inversely associated with ALS, suggesting that interleukin-1 inhibitors may lower the risk of this always fatal disease. The role of IL-2r alpha levels in ALS needs further verification in causal inference studies with larger sample sizes.