Body Mass Index, Interleukin-6 Signaling and Multiple Sclerosis: A Mendelian Randomization Study.

Objectives: We explored whether genetically predicted increased body mass index (BMI) modulates multiple sclerosis (MS) risk through interleukin-6 (IL-6) signaling. Methods: We performed a two-sample Mendelian randomization (MR) study using multiple genome-wide association studies (GWAS) datasets for BMI, IL-6 signaling, IL-6 levels and c-reactive protein (CRP) levels as exposures and estimated their effects on risk of MS from GWAS data from the International Multiple Sclerosis Genetics Consortium (IMSGC) in 14,802 MS cases and 26,703 controls. Results: In univariable MR analyses, genetically predicted increased BMI and IL-6 signaling were associated with higher risk of MS (BMI: odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.15-1.47, p = 3.76 × 10-5; IL-6 signaling: OR = 1.51, 95% CI = 1.11-2.04, p = 0.01). Furthermore, higher BMI was associated with increased IL-6 signaling (ß = 0.37, 95% CI = 0.32,0.41, p = 1.58 × 10-65). In multivariable MR analyses, the effect of IL-6 signaling on MS risk remained after adjusting for BMI (OR = 1.36, 95% CI = 1.11-1.68, p = 0.003) and higher BMI remained associated with an increased risk for MS after adjustment for IL-6 signaling (OR = 1.16, 95% CI =1.00-1.34, p = 0.046). The proportion of the effect of BMI on MS mediated by IL-6 signaling corresponded to 43% (95% CI = 25%-54%). In contrast to IL-6 signaling, there was little evidence for an effect of serum IL-6 levels or CRP levels on risk of MS. Conclusion: In this study, we identified IL-6 signaling as a major mediator of the association between BMI and risk of MS. Further explorations of pathways underlying the association between BMI and MS are required and will, together with our findings, improve the understanding of MS biology and potentially lead to improved opportunities for targeted prevention strategies.