Abstract
Introduction: Observational analyses have linked circulating inflammatory biomarkers with an increased risk of abdominal aortic aneurysms (AAA). Although observational studies implicate inflammatory biomarkers in AAA, whether these are a cause or consequence of the disease is unknown. A limited number of trials have explored agents that reduce inflammation in slowing the progression of AAA. Observational study quality may be limited by residual confounding and reverse causality. We sought to leverage genetic instruments and Mendelian Randomization (MR) to evaluate the human genetic evidence supporting inflammatory biomarkers in the pathogenesis of AAA. Methods: We leveraged a meta-analysis of 6 genome-wide association studies (GWAS) of 66 circulating inflammatory markers including up to 59,969 participants of European ancestry. We tested the association for each biomarker with AAA using summary statistics from a meta-analysis of 17 individual GWAS from 14 discovery cohorts in the AAAgen consortium comprising 39,221 individuals with AAA. We employed Wald ratio or inverse-variance weighted MR; weighted median and weighted mode methods were applied as sensitivity analyses. Results: After accounting for multiple testing by controlling the false discovery rate (q < 0.05), we identified a total of 6/66 (9.1%) inflammatory biomarkers that had a significant association with AAA: sIL6R, CCL8, CCL7, ILRN, F2, and PIGF. These results were consistent across a range of linkage-disequilibrium thresholds to identify independent genetic instruments. Some of these biomarkers have been previously implicated in the development of AAA but have not been validated in human RCTs of aneurysm development, growth, or rupture. Conclusions: This analysis highlights the role of several circulating inflammatory markers in the development of AAA. These findings represent potential therapeutic targets for further investigation in mechanistic trials.
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