TY - JOUR
T1 - Interleukin-6 receptor pathways in abdominal aortic aneurysm
AU - Harrison, Seamus C.
AU - Smith, Andrew J. P.
AU - Jones, Gregory T.
AU - Swerdlow, Daniel I.
AU - Rampuri, Riaz
AU - Bown, Matthew J.
AU - Folkersen, Lasse
AU - Baas, Annette F.
AU - de Borst, Gert Jan
AU - Blankensteijn, Jan D.
AU - Price, Jacqueline F.
AU - van der Graaf, Yolanda
AU - McLachlan, Stela
AU - Agu, Obi
AU - Hofman, Albert
AU - Uitterlinden, Andre G.
AU - Franco-Cereceda, Anders
AU - Ruigrok, Ynte M.
AU - van't Hof, F. N.
AU - Powell, Janet T.
AU - van Rij, Andre M.
AU - Casas, Juan P.
AU - Eriksson, Per
AU - Holmes, Michael V.
AU - Asselbergs, Folkert W.
AU - Hingorani, Aroon D.
AU - Humphries, Steve E.
PY - 2013/12/21
Y1 - 2013/12/21
N2 - 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. © The Author 2012.
AB - 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. © The Author 2012.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84891514939&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/23111417
U2 - https://doi.org/10.1093/eurheartj/ehs354
DO - https://doi.org/10.1093/eurheartj/ehs354
M3 - Article
C2 - 23111417
SN - 0195-668X
VL - 34
SP - 3707
EP - 3716
JO - European Heart journal
JF - European Heart journal
IS - 48
ER -