Additive Effects of Genetic Interleukin-6 Signaling Downregulation and Low-Density Lipoprotein Cholesterol Lowering on Cardiovascular Disease: A 2×2 Factorial Mendelian Randomization Analysis

Background Although trials suggest that anti‐inflammatory approaches targeting interleukin (IL)‐6 signaling can reduce cardiovascular risk, it remains unknown whether targeting IL‐6 signaling could reduce risk additively to low‐density lipoprotein cholesterol (LDL‐C) lowering. Here, we assess interactions in associations of genetic downregulation of IL‐6 signaling and LDL‐C lowering with lifetime cardiovascular disease risk. Methods and Results Genetic scores for IL‐6 signaling downregulation and LDL‐C lowering were used to divide 408 225 White British individuals in UK Biobank into groups of lifelong exposure to downregulated IL‐6 signaling, lower LDL‐C, or both. Associations with risk of cardiovascular disease (coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, vascular death) were explored in factorial Mendelian randomization. Compared with individuals with genetic IL‐6 and LDL‐C scores above the median, individuals with LDL‐C scores lower than the median but IL‐6 scores above the median had an odds ratio (OR) of 0.96 (95% CI, 0.93–0.98) for cardiovascular disease. A similar OR (0.96; 95% CI, 0.93–0.98) was estimated for individuals with genetic IL‐6 scores below the median but LDL‐C scores above the median. Individuals with both genetic scores lower than the median were at lower odds of cardiovascular disease (OR, 0.92; 95% CI, 0.90–0.95). There was no interaction between the 2 scores (relative excess risk attributed to interaction index, 0; synergy index, 1; P for multiplicative interaction=0.51). Genetic IL‐6 score below the median was associated with lower cardiovascular disease risk across measured LDL‐C strata ( Conclusions Genetically downregulated IL‐6 signaling and genetically lowered LDL‐C are associated with additively lower lifetime risk of cardiovascular disease. Future trials should explore combined IL‐6 inhibition and LDL‐C lowering treatments for cardiovascular prevention.