Background: 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. Methods: 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. Results: 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 (<InlineEquation ID="IEq1"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq1.gif" Format="GIF" Height="17" Rendition="HTML" Resolution="72" Type="Linedraw" Width="32" /> </InlineMediaObject> <EquationSource Format="TEX">${\beta }_{{Fit}}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi>β</mi> </mrow> <mrow> <mi>F</mi> <mi>i</mi> <mi>t</mi> </mrow> </msub> </math></EquationSource> </InlineEquation> = 0.21; 95% CI = [0.08; 0.33]; <InlineEquation ID="IEq2"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq2.gif" Format="GIF" Height="16" Rendition="HTML" Resolution="72" Type="Linedraw" Width="43" /> </InlineMediaObject> <EquationSource Format="TEX">${P}_{{FDR}}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi>P</mi> </mrow> <mrow> <mi>F</mi> <mi>D</mi> <mi>R</mi> </mrow> </msub> </math></EquationSource> </InlineEquation> = 0.035, <InlineEquation ID="IEq3"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq3.gif" Format="GIF" Height="19" Rendition="HTML" Resolution="72" Type="Linedraw" Width="38" /> </InlineMediaObject> <EquationSource Format="TEX">${\beta }_{{Age}1}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi>β</mi> </mrow> <mrow> <mi>A</mi> <mi>g</mi> <mi>e</mi> <mn>1</mn> </mrow> </msub> </math></EquationSource> </InlineEquation> = 0.13; 95% CI = [0.05; 0.21]; <InlineEquation ID="IEq4"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq2.gif" Format="GIF" Height="16" Rendition="HTML" Resolution="72" Type="Linedraw" Width="43" /> </InlineMediaObject> <EquationSource Format="TEX">${P}_{{FDR}}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi>P</mi> </mrow> <mrow> <mi>F</mi> <mi>D</mi> <mi>R</mi> </mrow> </msub> </math></EquationSource> </InlineEquation> = 0.019) and TRAIL (<InlineEquation ID="IEq5"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq1.gif" Format="GIF" Height="17" Rendition="HTML" Resolution="72" Type="Linedraw" Width="32" /> </InlineMediaObject> <EquationSource Format="TEX">${\beta }_{{Fit}}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi>β</mi> </mrow> <mrow> <mi>F</mi> <mi>i</mi> <mi>t</mi> </mrow> </msub> </math></EquationSource> </InlineEquation> = 0.09; 95% CI = [0.03; 0.15]; <InlineEquation ID="IEq6"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq2.gif" Format="GIF" Height="16" Rendition="HTML" Resolution="72" Type="Linedraw" Width="43" /> </InlineMediaObject> <EquationSource Format="TEX">${P}_{{FDR}}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi>P</mi> </mrow> <mrow> <mi>F</mi> <mi>D</mi> <mi>R</mi> </mrow> </msub> </math></EquationSource> </InlineEquation> = 0.045, <InlineEquation ID="IEq7"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq3.gif" Format="GIF" Height="19" Rendition="HTML" Resolution="72" Type="Linedraw" Width="38" /> </InlineMediaObject> <EquationSource Format="TEX">${\beta }_{{Age}1}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi>β</mi> </mrow> <mrow> <mi>A</mi> <mi>g</mi> <mi>e</mi> <mn>1</mn> </mrow> </msub> </math></EquationSource> </InlineEquation> = 0.09; 95% CI = [0.05; 0.13]; <InlineEquation ID="IEq8"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq2.gif" Format="GIF" Height="16" Rendition="HTML" Resolution="72" Type="Linedraw" Width="43" /> </InlineMediaObject> <EquationSource Format="TEX">${P}_{{FDR}}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi>P</mi> </mrow> <mrow> <mi>F</mi> <mi>D</mi> <mi>R</mi> </mrow> </msub> </math></EquationSource> </InlineEquation> = <InlineEquation ID="IEq9"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq9.gif" Format="GIF" Height="17" Rendition="HTML" Resolution="72" Type="Linedraw" Width="53" /> </InlineMediaObject> <EquationSource Format="TEX">$5\cdot {10}^{-4}$</EquationSource> <EquationSource Format="MATHML"><math> <mn>5</mn> <mo>⋅</mo> <msup> <mrow> <mn>10</mn> </mrow> <mrow> <mo>−</mo> <mn>4</mn> </mrow> </msup> </math></EquationSource> </InlineEquation>) and the negative association with SCF (<InlineEquation ID="IEq10"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq1.gif" Format="GIF" Height="17" Rendition="HTML" Resolution="72" Type="Linedraw" Width="32" /> </InlineMediaObject> <EquationSource Format="TEX">${\beta }_{{Fit}}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi>β</mi> </mrow> <mrow> <mi>F</mi> <mi>i</mi> <mi>t</mi> </mrow> </msub> </math></EquationSource> </InlineEquation> = _0.11; 95% CI = [−0.19; −0.03]; <InlineEquation ID="IEq11"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq2.gif" Format="GIF" Height="16" Rendition="HTML" Resolution="72" Type="Linedraw" Width="43" /> </InlineMediaObject> <EquationSource Format="TEX">${P}_{{FDR}}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi>P</mi> </mrow> <mrow> <mi>F</mi> <mi>D</mi> <mi>R</mi> </mrow> </msub> </math></EquationSource> </InlineEquation> = 0.121, <InlineEquation ID="IEq12"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq3.gif" Format="GIF" Height="19" Rendition="HTML" Resolution="72" Type="Linedraw" Width="38" /> </InlineMediaObject> <EquationSource Format="TEX">${\beta }_{{Age}1}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi>β</mi> </mrow> <mrow> <mi>A</mi> <mi>g</mi> <mi>e</mi> <mn>1</mn> </mrow> </msub> </math></EquationSource> </InlineEquation> = −0.11; 95% CI = [−0.17; −0.06]; <InlineEquation ID="IEq13"> <InlineMediaObject> <ImageObject Color="BlackWhite" FileRef="43856_2025_1124_Article_IEq2.gif" Format="GIF" Height="16" Rendition="HTML" Resolution="72" Type="Linedraw" Width="43" /> </InlineMediaObject> <EquationSource Format="TEX">${P}_{{FDR}}$</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi>P</mi> </mrow> <mrow> <mi>F</mi> <mi>D</mi> <mi>R</mi> </mrow> </msub> </math></EquationSource> </InlineEquation> = 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. Conclusions: 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.

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

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2025年9月11日

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Dennis Freuer,
Jakob Linseisen,
Timo Schmitz,
Barbara Thorand,
Annette Peters,
Agnese Petrera,
Margit Heier,
Christa Meisinger

摘要

Background:

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.

Methods:

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.

Results:

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 ( ${\beta }_{{Fit}}$ $β_{F i t}$ = 0.21; 95% CI = [0.08; 0.33]; ${P}_{{FDR}}$ $P_{F D R}$ = 0.035, ${\beta }_{{Age}1}$ $β_{A g e 1}$ = 0.13; 95% CI = [0.05; 0.21]; ${P}_{{FDR}}$ $P_{F D R}$ = 0.019) and TRAIL ( ${\beta }_{{Fit}}$ $β_{F i t}$ = 0.09; 95% CI = [0.03; 0.15]; ${P}_{{FDR}}$ $P_{F D R}$ = 0.045, ${\beta }_{{Age}1}$ $β_{A g e 1}$ = 0.09; 95% CI = [0.05; 0.13]; ${P}_{{FDR}}$ $P_{F D R}$ = $5\cdot {10}^{-4}$ $5 \cdot 10^{- 4}$ ) and the negative association with SCF ( ${\beta }_{{Fit}}$ $β_{F i t}$ = ^_0.11; 95% CI = [−0.19; −0.03]; ${P}_{{FDR}}$ $P_{F D R}$ = 0.121, ${\beta }_{{Age}1}$ $β_{A g e 1}$ = −0.11; 95% CI = [−0.17; −0.06]; ${P}_{{FDR}}$ $P_{F D R}$ = 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.

Conclusions:

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.