---
title: "IL6RA Asp358Ala-modeled mice show protection from atherosclerosis and abdominal aortic aneurysm"
id: "biorxiv-2-modelling-the-human-il6ra-asp358ala-variant-in-mice-effects-on-atherosclerosis"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-2-modelling-the-human-il6ra-asp358ala-variant-in-mice-effects-on-atherosclerosis"
content_type: "clinical_feed_article"
specialty: "Cardiology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.10.16.759391v1?rss=1"
published_at: "2026-10-21T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# IL6RA Asp358Ala-modeled mice show protection from atherosclerosis and abdominal aortic aneurysm
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-2-modelling-the-human-il6ra-asp358ala-variant-in-mice-effects-on-atherosclerosis
- **Specialty:** [Cardiology](https://medichelpline.com/clinical-feed/cardiology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.10.16.759391v1?rss=1)
- **Published At:** 2026-10-21T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Investigators introduced the orthologous IL6RA Glu357Ala substitution into male mice to model the human **IL6RA Asp358Ala** variant. - The engineered mice displayed the same alteration in **soluble IL6RA** levels that has been reported in humans carrying the Asp358Ala allele. - The study team observed a significant reduction in both **atherosclerosis** and **abdominal aortic aneurysm (AAA)** in the mutant male mice compared with controls. - The authors referenced a recent clinical report in which **ziltivekimab**, a neutralising anti-IL6 antibody, failed to lower major adverse cardiovascular events in patients with ASCVD and chronic kidney disease. - Data indicated that simply neutralising IL6 with that antibody did not mirror the genetic variant’s effect, prompting the authors to argue that therapies must more closely reproduce the variant’s biological effect on IL6 signalling. - The source did not specify detailed experimental dosing regimens, full methodological protocols, or wider demographic (female or aged-matched) animal cohorts in the abstract text provided; those details were not reported in the source abstract.
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Minoru Takaoka 1 University of Cambridge; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Minoru%2BTakaoka%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Takaoka%20M&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMinoru%2BTakaoka%2B) Rahul Sharma 1 University of Cambridge; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Rahul%2BSharma%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Sharma%20R&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ARahul%2BSharma%2B) Fabien Lareyre 2 Department of Vascular Surgery, Hospital of Antibes; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Fabien%2BLareyre%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Lareyre%20F&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AFabien%2BLareyre%2B) Marc Clement 3 Universite Paris Cite and Universite Sorbonne Paris Nord, Institut National de la Sante et de la Recherche Medicale U1148, Laboratory for vascular translational science * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Marc%2BClement%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Clement%20M&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMarc%2BClement%2B) James Harrison 1 University of Cambridge; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=James%2BHarrison%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Harrison%20J&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AJames%2BHarrison%2B) Leanne Masters 1 University of Cambridge; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Leanne%2BMasters%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Masters%20L&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ALeanne%2BMasters%2B) Yuning Lu 1 University of Cambridge; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Yuning%2BLu%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Lu%20Y&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AYuning%2BLu%2B) Dirk Paul 1 University of Cambridge; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Dirk%2BPaul%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Paul%20D&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ADirk%2BPaul%2B) Ziad Mallat 1 University of Cambridge; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Ziad%2BMallat%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Mallat%20Z&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AZiad%2BMallat%2B) * For correspondence: zm255@medschl.cam.ac.uk * [Abstract](https://www.biorxiv.org/content/10.64898/2026.10.16.759391v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5890990/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.10.16.759391v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5890990/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.10.16.759391v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5890990/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.10.16.759391v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5890990/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## Abstract The association of IL6RA Asp358Ala variant with reduced risk of atherosclerotic cardiovascular disease (ASCVD) and abdominal aortic aneurysm (AAA) prompted interest in targeting IL6 signalling in these conditions. A recent report that ziltivekimab, a neutralising anti-IL6 antibody, did not reduce major adverse cardiovascular events in patients with ASCVD and chronic kidney disease, has cast doubt on the causal role of IL6 signalling in ASCVD. Here, we show that introducing the orthologous IL6RA Glu357Ala substitution in male mice leads to the same alteration in soluble IL6RA levels seen in humans, and significantly prevents atherosclerosis and AAA. Thus, therapies that more closely reproduce the biological effects of the IL6RA Asp358Ala variant on IL6 signalling are needed to reduce cardiovascular risk in humans. ### Competing Interest Statement The authors have declared no competing interest. ## Funder Information Declared British Heart Foundation, https://ror.org/02wdwnk04, 10/001/27642 BHF Cambridge Centre of Excellence, RE/24/130011 Leducq Foundation Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY 4.0 International license](http://creativecommons.org/licenses/by/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. 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[ Download PDF](https://www.biorxiv.org/content/10.64898/2026.10.16.759391v1.full.pdf) Print/Save Options [Download PDF](https://www.biorxiv.org/content/biorxiv/early/2026/10/21/2026.10.16.759391.full.pdf)Full Text & In-line FiguresXML [More Info](https://www.biorxiv.org/about/FAQ#PrintOptions "More Information on Print/Save Options") [ Email](https://www.biorxiv.org/ "Email this Article") [ Share](https://www.biorxiv.org/) Modelling the human IL6RA Asp358Ala variant in mice: effects on atherosclerosis and abdominal aortic aneurysm Minoru Takaoka, Rahul Sharma, Fabien Lareyre, Marc Clement, James Harrison, Leanne Masters, Yuning Lu, Dirk Paul, Ziad Mallat bioRxiv 2026.10.16.759391; doi: https://doi.org/10.64898/2026.10.16.759391 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. 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