Human genetic evidence to inform clinical development of interleukin-6 signaling inhibition for abdominal aortic aneurysm

Abstract

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 interleukin-6 (IL6) signaling inhibition for treatment of AAA. Methods We focused on rs2228145, a missense variant in the IL6R gene region whose associations are expressed per additional copy of the C allele, corresponding to the genetically-predicted effect of IL6 signaling inhibition. We consider genetic associations with AAA risk in the AAAgen consortium (39,221 cases, 1,086,107 controls) and UK Biobank (2215 cases, 365,428 controls). To validate against known effects of IL6 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 evaluated associations with measures of the abdominal aorta in UK Biobank, and explored genetic associations in clinically-relevant subgroups of the population. Results We observed strong genetic associations with AAA risk in the AAAgen consortium and in UK Biobank: odds ratio (OR) 0.91 (95% confidence interval [CI]: 0.90 to 0.92, p = 4x10-30) and OR 0.90 (95% CI: 0.84, 0.96, p=0.0007), respectively. The association with AAA risk in UK Biobank was linear in the number of minor alleles: OR 0.91 (95% CI: 0.83, 1.00) in heterozygotes and OR 0.80 (95% CI: 0.71, 0.92) in minor homozygotes. 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 rheumatologic disorders for which IL6 inhibitors have been approved. No strong associations were observed with thoracic aortic aneurysm, intracranial aneurysm, or abdominal aorta diameter in the general population without AAA. Associations attenuated towards the null in populations with concomitant inflammatory or connective tissue disease. Conclusions This drug target Mendelian randomization study supports that IL6 signaling inhibition will be efficacious for treating AAA, but not other types of aneurysmal disease. These findings serve to help inform clinical development of IL6 signaling inhibition for AAA treatment.