Human Genetic Evidence to Inform Clinical Development of IL-6 Signaling Inhibition for Abdominal Aortic Aneurysm

BACKGROUND: Abdominal aortic aneurysm (AAA) represents a significant cause of mortality, yet no medical therapies have proven efficacious. The aim of the current study was to leverage human genetic evidence to inform clinical development of IL-6 (interleukin-6) signaling inhibition for the treatment of AAA. METHODS: Associations of rs2228145, a missense variant in the IL6R gene region, are expressed per additional copy of the C allele, corresponding to the genetically predicted effect of IL-6 signaling inhibition. We consider genetic associations with AAA risk in the AAAgen consortium (39 221 cases and 1 086 107 controls) and UK Biobank (1963 cases and 365 680 controls). To validate against known effects of IL-6 signaling inhibition, we present associations with rheumatoid arthritis, polymyalgia rheumatica, and severe COVID-19. To explore mechanism specificity, we present associations with thoracic aortic aneurysm, intracranial aneurysm, and coronary artery disease. We further explored genetic associations in clinically relevant subgroups of the population. RESULTS: We observed strong genetic associations with AAA risk in the AAAgen consortium, UK Biobank, and FinnGen (odds ratios: 0.91 [95% CI, 0.90–0.92], P =4×10 −30 ; 0.90 [95% CI, 0.84–0.96], P =0.001; and 0.86 [95% CI, 0.82–0.91], P =7×10 −9 , respectively). The association was similar for fatal AAA but with greater uncertainty due to the lower number of events. The association with AAA was of greater magnitude than associations with coronary artery disease and even rheumatological disorders for which IL-6 inhibitors have been approved. No strong associations were observed with thoracic aortic aneurysm or intracranial aneurysm. Associations attenuated toward the null in populations with concomitant rheumatological or connective tissue disease. CONCLUSIONS: Inhibition of IL-6 signaling is a promising strategy for treating AAA but not other types of aneurysmal disease. These findings serve to help inform clinical development of IL-6 signaling inhibition for AAA treatment.