Pleiotropic effects between statin intake and inflammation parameters in two distinct population-based studies

Besides their lipid lowering effects, statins exhibit numerous beneficial and adverse effects (so called pleiotropic effects). A major pleiotropic effect of statins is their anti-inflammatory properties, but the impact on a wide range of inflammation-related proteins involved in specific metabolic pathways remains inconclusive. Therefore, in this study we examined the association between statin use and numerous circulating levels of inflammation-related proteins using data from two independent population-based studies.

The association between statin intake and up to 90 inflammation-related proteins (Olink Proteomics) were investigated in 803 and 1008 participants of the KORA-Fit and KORA-Age1 studies, respectively (overall age range: 53-93 years, 52% women). Association-specific multivariable parametric as well as non-parametric regression models were performed to obtain robust estimates. Confounding factors were selected using directed acyclic graphs and the potential effect of unmeasured confounding was assessed.

After adjustment for multiple testing, 3 and 8 associations remain in the KORA-Fit and KORA-Age1 studies, respectively. The strongest evidence (in terms of effect size, replication, and robustness) is found for the positive associations with the inflammation-related proteins TRANS ( ${\beta }_{Fit}$  = 0.21; 95% CI = [0.08; 0.33]; $P_{FDR}$  = 0.035, ${\beta }_{Age1}$  = 0.13; 95% CI = [0.05; 0.21]; $P_{FDR}$  = 0.019) and TRAIL ( ${\beta }_{Fit}$  = 0.09; 95% CI = [0.03; 0.15]; $P_{FDR}$  = 0.045, ${\beta }_{Age1}$  = 0.09; 95% CI = [0.05; 0.13]; $P_{FDR}$  =  $5\cdot {10}^{-4}$ ) and the negative association with SCF ( ${\beta }_{Fit}$  = ^_0.11; 95% CI = [-0.19; -0.03]; $P_{FDR}$  = 0.121, ${\beta }_{Age1}$  = -0.11; 95% CI = [-0.17; -0.06]; $P_{FDR}$  = 0.003). Further associations with NT-3, MMP-10, uPA, and CD244 found in one of the studies are consistent with the point estimates of the other study.

The present study identifies associations between statin intake and inflammation-related proteins pointing to certain metabolic pathways. The results could contribute to a better understanding of the mechanisms underlying the pleiotropic effect of statins.