Interleukin-6 receptor pathways in abdominal aortic aneurysm.

Seamus C Harrison; Andrew JP Smith; Gregory T Jones; Daniel I Swerdlow; Riaz Rampuri; Matthew J Bown; Aneurysm Consortium; Lasse Folkersen; Annette F Baas; Gert Jan de Borst; +18 more... Jan D Blankensteijn; Jacqueline F Price; Yolanda van der Graaf; Stela McLachlan; Obi Agu; Albert Hofman; Andre G Uitterlinden; Anders Franco-Cereceda; Ynte M Ruigrok; FN van't Hof; Janet T Powell; Andre M van Rij; Juan P Casas; Per Eriksson; Michael V Holmes; Folkert W Asselbergs; Aroon D Hingorani; Steve E Humphries; (2013) Interleukin-6 receptor pathways in abdominal aortic aneurysm. European heart journal, 34 (48). pp. 3707-3716. ISSN 0195-668X DOI: 10.1093/eurheartj/ehs354
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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.


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