P900 Studying causality association of ustekinumab with cardiovascular disease outcomes using Mendelian randomization
Miguel González, J.A.(1)*;Sánchez Mayor, M.(1);Cervera Seco, L.M.(1);Gaite Reguero, A.(1);Pavlidis, P.(2);Martínez Marigorta, U.(1);
(1)CIC bioGUNE, Integrative Genomics, Bilbao, Spain;(2)King's College London, Immunology, London, United Kingdom;
Background
The human antibody ustekinumab targets the common p40 subunit between both pro-inflammatory interleukin-12 (IL-12) and interleukin-23 (IL-23) that upregulate T cell differentiation towards T helper 1 (TH1) and T helper 17 (TH17) respectively. The blockade of the IL12-IL23 pathway has been shown to be an effective therapeutic option for Inflammatory Bowel Disease treatment, however a recent epidemiological study has reported a potential cardiovascular risk association for ustekinumab treatment in patients at high cardiovascular risk specifically1. We use mendelian randomization (MR) to assess the reliability of this finding.
Methods
MR uses genetic variation to examine the causal effect of a risk factor (exposure) on a disease (outcome). The basis of MR relies on the use of genetic variants as instrumental variables (IVs) that are reliably related to the risk factor and that are not susceptible of reverse causation and confounding2. We use genetic variants (SNPs) detected in eQTL studies that affect gene expression levels as proxies for the IL12-IL23 pathway genes in order to simulate the biological effect of ustekinumab. A cardiovascular trait-composition composed of different groups of outcomes (acute coronary syndrome, transient ischaemic attack, unstable angina and ischemic stroke) was created to investigate further the possible association of ustekinumab with triggering cardiovascular events.
Results
Using top cis-eQTLs from the eQTLGen consortium and the Database of Immune Cell Expression (DICE) as IVs for the IL12-IL23 pathway genes, we observed non-significant associations after multiple testing correction for any of the cardiovascular traits. However, we observed a significant positive causal effect for IL12Rβ1 gene in acute coronary syndrome when using IVs from the Genotype-Tissue Expression (GTEx) project. An observation that was also obtained in a meta-analysis specifically for acute coronary syndrome. In addition, we run MR with multiple SNPs associated with IL12-IL23 genes and we did obtain similar results for IL12Rβ1 and acute coronary syndrome.
Conclusion
Our results suggest that the blockade of the IL12-IL23 pathway with ustekinumab might reduce cardiovascular risk and provide a cardioprotective effect based on the results obtained for acute coronary syndrome. As these results are not in line with previous observational studies1, further investigations are needed to clarify the biological mechanism that may account for these discrepancies.
1. Poizeau et al. JAMA Dermatol (2020).
2. Sanderson et al. Nat Rev (2022).
- Posted in: Poster Presentations: Genetics 2023