Extended Data Fig. 3: Genetic validation of IL-6 signaling inhibition effects using Mendelian randomization compared with ziltivekimab treatment in the RESCUE trial.
From: IL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk
Inverse-variance weighted Mendelian randomization associations of genetically proxied downregulation of IL-6 signaling through perturbation in IL6 using the (a) 8- and (b) 3-variant instruments (scaled to 25% and 12% decrease in CRP levels, respectively) with 8 circulating biomarkers measured in RESCUE trial. Data are presented as logchanges (% change) in levels; error bars correspond to 95% confidence intervals. IL6 genetic instrument derived from CRP GWAS (UK Biobank + CHARGE; n = 575,531), Biomarker associations derived from multiple GWAS datasets as detailed in Supplementary Table 1 (sample sizes vary by biomarker). RESCUE effects from n = 66 per group (30 mg ziltivekimab versus placebo). Correlations of the effects of the (c) 8- and (d) 3-variant IL6 genetic instrument (CRP GWAS, UK Biobank+CHARGE; n = 575,531) and ziltivekimab in RESCUE (30 mg ziltivekimab versus placebo; n = 66 per group) on the 8 biomarkers (Spearman’s ρ = 0.90 and 0.87, respectively). Each point represents an effect estimate for a biomarker, as derived by inverse-variance weighted Mendelian randomization with horizontal and vertical error bars indicating the 95% confidence intervals (CI) for genetic instrument and ziltivekimab effects, respectively. All reported p-values are two-sided. Abbreviations: CRP, C-reactive protein; IL-6, interleukin-6; CI, confidence interval; OR, odds ratio; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; SAA, serum amyloid A; Lp(a), lipoprotein(a); ApoB, apolipoprotein B; ApoA, apolipoprotein A; GWAS, genome-wide association study; CHARGE, Cohorts for Heart and Aging Research in Genomic Epidemiology.
