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.
Findings
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.