Abstract 65: Interleukin-6 Signaling and Abdominal Aortic Aneurysm
Abdominal aortic aneurysm (AAA) is a common disease that predisposes to aortic rupture, which has a high mortality. The only intervention that is proven to reduce rupture is invasive surgery. Understanding causal disease pathways may allow development of non-surgical therapies to target AAA formation, progression or rupture. In this study we investigate the role of interleukin-6 and AAA.
We performed systematic review and meta-analysis of the published literature in order to determine the association between circulating interleukin-6 (IL-6) and presence of AAA. We then investigated the association between a common non-synonymous variant in the interleukin-6 receptor gene (IL6R) and presence of AAA, performed in vitro functional analyses of this variant, and expression studies in aortic tissue.
Meta-analysis of seven case-control studies of AAA (infra-renal aortic diameter ≥ 3cm), pooling data from 869 cases and 851 controls demonstrated consistently higher levels of circulating IL-6 in AAA compared to controls (standardised mean difference (SMD) = 0.42 units, 95% CI = 0.32-0.52, I2 = 69.4%, P for fixed effects = 1.29 x 10-16, P for random effects = 1.2 x10-5). There was less heterogeneity when comparing large AAA (>5cm, n = 547), to disease free controls (n = 712) (SMD = 0.46 units, 95% CI 0.34-0.57, I2=31.5, P = 2.2 x 10-14). The rare allele of rs7529229, which tags the non-synonymous variant (p.Asp358Ala, rs2228154) was consistently associated with reduced risk of AAA in meta-analysis of 4 studies, pooling data from 4,708 cases and 15,816 (per allele odds ratio 0.84, 95% CI 0.80-0.89, P = 2.7 x 10-11, I2=0). This variant was also associated with reduced risk incident AAA endpoints (rupture +/- repair) in prospective analysis of 7,888 individuals with known arterial disease (hazard ratio = 0.81, 95% CI 0.67 - 0.99, P = 0.043). Expression studies revealed strong correlation between IL-6 expression target genes (STAT3, MYC, ATF3, BCL3 and ICAM1) in aortic adventitia. In vitro analyses demonstrate that in lymphoblastoid cells, there is a genotype specific reduction in expression of downstream mediators of IL-6 signalling in response to IL-6 stimulation.
These data indicate that signalling via the IL-6 receptor is likely to be causal in the development of AAA. This suggests that this pathway may represent a novel target for pharmacological treatment of AAA with biological agents such as Tocilizumab, and clinical trials to assess this may be warranted.
- © 2012 by American Heart Association, Inc.