MethodsWe conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo.Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach.ResultsUp to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25-0.66, I2 = 70%, P = 1.1 × 10-5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80-0.89, I2 = 0%, P = 2.7 × 10-11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers.ConclusionsA Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management.

Abdominal aortic aneurysm, Interleukin-6, Mendelian randomization, Polymorphism
dx.doi.org/10.1093/eurheartj/ehs354, hdl.handle.net/1765/67782
European Heart Journal
Erasmus MC: University Medical Center Rotterdam

Harrison, S.C, Smith, A.J, Jones, G.T, Swerdlow, D.I, Rampuri, R, Bown, N, … Humphries, S.E. (2013). Interleukin-6 receptor pathways in abdominal aortic aneurysm. European Heart Journal, 34(48), 3707–3716. doi:10.1093/eurheartj/ehs354