| Title: | A multi-omics approach uncovers causality of IL6R on endotypes of subclinical carotid atherosclerosis and the possible role of the IL6R/OSMR pathway |
| Journal: | Cardiovascular Research |
| Published: | 22 Oct 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41124095/ |
| DOI: | https://doi.org/10.1093/cvr/cvaf177 |
Publication 16673
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Abstract
AIMS: Endotypes integrate individual clinical and molecular data and can be used to formulate molecular subclassifications of diseases. We previously derived four endotypes of subclinical carotid atherosclerosis in a large European cohort, c-IMT and c-IMT Progression as Predictors of Vascular Events in a High-Risk European Population (IMPROVE), identifying individuals with a specific cardiovascular (CV) risk, ranging from low (endotype 1) to very high (endotype 4). Here, we investigate the mechanisms underlying the differences in CV risk observed across these four endotypes.</p>
METHODS AND RESULTS: We validated the four endotypes in SCAPIS (n = 5050) and UK Biobank (n = 50 396) using carotid plaque and carotid intima-media thickness (c-IMT) as subclinical atherosclerosis measures. Endotype 4 associated with a larger number of carotid plaques and increased c-IMT measures as compared to endotype 1. We performed a meta-analysis of individual genome wide association studies in IMPROVE (n = 3711), SCAPIS and UK Biobank, and identified 12 SNPs associated with endotypes. We investigated if they regulated gene expression and circulating protein levels. We found that rs2228145A/C at Interleukin-6 Receptor (IL6R), associated with endotype 4, regulated IL6R expression and circulating levels of OncoStatin M Receptor (OSMR), Complement Factor B (CFB) and Fibrinogen Chain A (FGA). We used rs2228145A/C as an instrument in two-sample Mendelian randomization analyses and showed that a decreasing IL6R expression, associated with increasing CFB, FGA, and OSMR circulating levels. Endotype 4, IL6R, CFB, FGA, and OSMR co-localized within 250 kb surrounding rs2228145A/C. However, only OSMR was up-regulated in advanced carotid atherosclerotic plaques in the presence of the A allele and in aortic region exposed to low wall shear stress. In the UK Biobank, we observed that each additional A allele at rs2228145 increased by 1.28-times the risk of myocardial infarction (MI) in endotype 4.</p>
CONCLUSION: Rs2228145A/C associated with endotype 4 clinical and molecular characteristics and amplified the MI risk in individuals assigned to endotype 4. These effects appeared to be mediated by a crosstalk with OSMR.</p>
21 Authors
- Qiao Sen Chen
- Hanna M Björck
- Otto Bergman
- Damiano Baldassarre
- Gunnar Engström
- Antonio Gallo
- Anders Gummesson
- Ulf Hedin
- Sudhir Kurl
- Lars Lind
- Ljubica Matic
- Douw Johannes Mulder
- Matteo Pirro
- Kai Savonen
- Stefan Söderberg
- Fabrizio Veglia
- Elena Tremoli
- Carl Johan Östgren
- Per Eriksson
- Rona J Strawbridge
- Bruna Gigante
1 Application
| Application ID | Title |
|---|---|
| 71392 | Investigating complex relationships between genetics, exposures, biomarkers, endophenotypes and cardiometabolic, inflammatory, immune and brain-related health outcomes |
Enabling scientific discoveries that improve human health