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Mendelian Randomization Reveals Interleukin-6 Receptor-Lipoprotein(a) Interplay With Independent Cardiovascular Risk
Azin Kheirkhah1, Silvia Di Maio1, Stefan Coassin1
1Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.
JACC. Basic to Translational Science
|May 8, 2026
Summary
Interleukin-6 receptor (IL-6R) signaling causally influences Lp(a) levels, a cardiovascular disease risk factor. Considering IL-6R
Area of Science:
- Genetics and Cardiovascular Disease Research
- Molecular Biology and Biomarkers
Background:
- Cardiovascular disease (CVD) remains a leading cause of mortality globally.
- Interleukin-6 receptor (IL-6R) signaling and lipoprotein(a) [Lp(a)] are implicated as causal risk factors for CVD.
- The precise relationship between IL-6R signaling, IL-6 levels, and Lp(a) concentrations requires elucidation.
Purpose of the Study:
- To investigate the causal effect of IL-6R signaling on Lp(a) concentrations using Mendelian randomization.
- To examine whether the functional state of IL-6R confounds the association between IL-6 and Lp(a).
- To assess the independent and combined effects of IL-6R signaling and Lp(a) on CVD risk.
Main Methods:
- Two-sample Mendelian randomization (MR) was employed to assess the causal effect of IL-6R signaling on Lp(a).
- Epidemiological analyses using UK Biobank data were conducted to evaluate confounding effects.
- Factorial MR was utilized to determine the independent contributions of IL-6R signaling and Lp(a) to CVD risk.
Main Results:
- Mendelian randomization provided evidence for a causal effect of IL-6R signaling on Lp(a) concentrations.
- Epidemiological analyses revealed that the functional state of IL-6R can confound the IL-6 and Lp(a) association.
- The direct effect of circulating IL-6 on Lp(a) was modest, even when accounting for IL-6R status.
- Factorial MR indicated that reduced IL-6R signaling and lower Lp(a) independently decrease CVD risk.
Conclusions:
- IL-6R signaling exerts a causal influence on Lp(a) concentrations, highlighting a direct interplay between these CVD risk factors.
- Accounting for IL-6R functional state is crucial to avoid confounding the association between IL-6 and Lp(a).
- Independent down-regulation of IL-6R signaling and Lp(a) present complementary strategies for cardiovascular disease risk reduction.
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