Interleukin-6 receptor pathways in abdominal aortic aneurysm.
Harrison SC., Smith AJP., Jones GT., Swerdlow DI., Rampuri R., Bown MJ., Aneurysm Consortium None., Folkersen L., Baas AF., de Borst GJ., Blankensteijn JD., Price JF., van der Graaf Y., McLachlan S., Agu O., Hofman A., Uitterlinden AG., Franco-Cereceda A., Ruigrok YM., van't Hof FN., Powell JT., van Rij AM., Casas JP., Eriksson P., Holmes MV., Asselbergs FW., Hingorani AD., Humphries SE.
METHODS: We 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. RESULTS: Up 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, I(2) = 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, I(2) = 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. CONCLUSIONS: A 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.