期刊
EUROPEAN HEART JOURNAL
卷 34, 期 48, 页码 3707-3716出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehs354
关键词
Abdominal aortic aneurysm; Mendelian randomization; Interleukin-6; Polymorphism
资金
- BHF clinical training fellowship [FS/11/16/28696]
- BHF [RG2008/08, FS 05/125]
- Wellcome Trust [076113, 085475]
- Higher Education Funding Council for England
- Leicester NIHR Biomedical Research Unit in Cardiovascular Disease
- British Heart Foundation
- Chief Scientist Office for Scotland
- BBMRI-NL
- Dutch government [NWO 184.021.007]
- Netherlands Organisation for Health Research and Development (ZonMw grant) [90700342]
- Netherlands Heart Foundation [2009T001]
- Health Research Council of New Zealand
- MRC population health scientisist [G0802432]
- UK Medical Council Doctoral Training Award
- Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly [014-93-015, RIDE2]
- Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]
- Erasmus Medical Center and Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- MRC [G0802432] Funding Source: UKRI
- British Heart Foundation [FS/13/6/29977, FS/11/16/28696, RG/10/12/28456, PG/09/022/26739] Funding Source: researchfish
- Medical Research Council [G0802432] Funding Source: researchfish
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. 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 0.250.66, I-2 70, P 1.1 105 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: 0.800.89, I-2 0, P 2.7 1011). 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. 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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