title: Interleukin-6 receptor pathways in abdominal aortic aneurysm.
abstract: 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.
authors.affiliation: Department of Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, Rayne Building, University Street, London WC1E 6JJ, UK.
authors.forename: Seamus C
authors.initials: SC
authors.lastname: Harrison
authors.forename: Andrew J P
authors.initials: AJ
authors.lastname: Smith
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Jones
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Swerdlow
authors.forename: Riaz
authors.initials: R
authors.lastname: Rampuri
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bown
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.forename: Annette F
authors.initials: AF
authors.lastname: Baas
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: de Borst
authors.forename: Jan D
authors.initials: JD
authors.lastname: Blankensteijn
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Price
authors.forename: Yolanda
authors.initials: Y
authors.lastname: van der Graaf
authors.forename: Stela
authors.initials: S
authors.lastname: McLachlan
authors.forename: Obi
authors.initials: O
authors.lastname: Agu
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.forename: Ynte M
authors.initials: YM
authors.lastname: Ruigrok
authors.forename: F N
authors.initials: FN
authors.lastname: van't Hof
authors.forename: Janet T
authors.initials: JT
authors.lastname: Powell
authors.forename: Andre M
authors.initials: AM
authors.lastname: van Rij
authors.forename: Juan P
authors.initials: JP
authors.lastname: Casas
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Michael V
authors.initials: MV
authors.lastname: Holmes
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D000368:Aged; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism*; D002460:Cell Line; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D015850:Interleukin-6; D016271:Proto-Oncogene Proteins c-myc; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D018799:Intercellular Adhesion Molecule-1
keywords: Abdominal aortic aneurysm; Interleukin-6; Mendelian randomization; Polymorphism