Associations of the circulating levels of cytokines with risk of amyotrophic lateral sclerosis: a Mendelian randomization study

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that is accompanied by muscle weakness and muscle atrophy, typically resulting in death within 3-5 years from the disease occurrence. Though the cause of ALS remains unclear, increasing evidence has suggested that inflammation is involved in the pathogenesis of ALS. Thus, we performed two-sample Mendelian randomization (MR) analyses to estimate the associations of circulating levels of cytokines and growth factors with the risk of ALS.

Methods: Genetic instrumental variables for circulating cytokines and growth factors were identified from a genome-wide association study (GWAS) of 8293 European participants. Summary statistics of ALS were obtained from a GWAS including 20,806 ALS cases and 59,804 controls of European ancestry. We used the inverse-variance weighted (IVW) method as the primary analysis. To test the robustness of our results, we further performed the simple-median method, weighted-median method, MR-Egger regression, and MR pleiotropy residual sum and outlier test. Finally, a reverse MR analysis was performed to assess the possibility of reverse causation between ALS and the cytokines that we identified.

Results: After Bonferroni correction, genetically predicted circulating level of basic fibroblast growth factor (FGF-basic) was suggestively associated with a lower risk of ALS [odds ratio (OR): 0.74, 95% confidence interval (95% CI): 0.60-0.92, P = 0.007]. We also observed suggestive evidence that interferon gamma-induced protein 10 (IP-10) was associated with a 10% higher risk of ALS (OR: 1.10, 95% CI: 1.03-1.17, P = 0.005) in the primary study. The results of sensitivity analyses were consistent.

Conclusions: Our systematic MR analyses provided suggestive evidence to support causal associations of circulating FGF-basic and IP-10 with the risk of ALS. More studies are warranted to explore how these cytokines may affect the development of ALS.