Lareyre, F. | Search bioRxiv

bioRxiv2026

Modelling the human IL6RA Asp358Ala variant in mice: effects on atherosclerosis and abdominal aortic aneurysm

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.

pathology↗

bioRxiv2018

Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates

BackgroundThe Asp358Ala variant (rs2228145; A>C) in the interleukin-6 receptor (IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth, and to assess the effect of blocking the IL-6 signalling pathway in mouse models of aneurysm rupture.\n\nMethodUsing data from 2,863 participants with AAA from nine prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/year). In a series of complementary randomised trials in mice, the effect of blocking the IL-6 signalling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter and time to aortic rupture and death.\n\nResultsAfter adjusting for age and sex, baseline aneurysm size was 0.55mm (95% confidence interval [CI]: 0.13, 0.98mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. There was no evidence of a reduction in AAA growth rate (change in growth=-0.06mm per year [-0.18, 0.06] per copy of the minor allele). In two mouse models of AAA, selective blockage of the IL-6 trans-signalling pathway, but not combined blockage of both, the classical and trans-signalling pathways, was associated with improved survival (p<0.05).\n\nConclusionsOur proof-of-principle data are compatible with the concept that IL-6 trans-signalling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.

genetics↗