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Int J Mol Epidemiol Genet 2011;2(3):261-285

Original Article
Prospective study of insulin-like growth factor-I, insulin-like growth factor-
binding protein 3, genetic variants in the IGF1 and IGFBP3 genes and risk of
coronary artery disease

Sally L. Ricketts, Katrijn L. Rensing, Jeff M. Holly, Li Chen, Elizabeth H. Young, Robert Luben, Sofie Ashford, Kijoung Song, Xin
Yuan, Abbas Dehghan, Benjamin J. Wright, Dawn M. Waterworth, Vincent Mooser, GEMS Investigators, Gérard Waeber, Peter
Vollenweider, Stephen E. Epstein, Mary S. Burnett, Joseph M. Devaney, Hakon H. Hakonarson, Daniel J. Rader, Muredach P.
Reilly, John Danesh, Simon G. Thompson, Alison M. Dunning, Cornelia M. van Duijn, Nilesh J. Samani, Ruth McPherson,
Nicholas J. Wareham, Kay-Tee Khaw, S. Matthijs Boekholdt, Manjinder S. Sandhu

Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK;
Departments of Vascular Medicine & Cardiology, Academic Medical Center, Amsterdam, The Netherlands; University
Department of Clinical Science at North Bristol, Southmead Hospital, Westbury-on-Trym, Bristol, UK; Division of Cardiology,
University of Ottawa Heart Institute, Ottawa, ON, Canada;  Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Genetics
Division, GlaxoSmithKline R&D, King of Prussia, PA, USA; Department of Epidemiology, Erasmus Medical Center, Rotterdam,
The Netherlands; Departments of Health Sciences and Genetics, University of Leicester, Leicester, UK; Members listed at end
of manuscript; Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington, DC, USA; The
Center for Applied Genomics, Children’s Hospital of Philadelphia, PA, USA; The Institute for Translational Medicine and
Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; The Cardiovascular Institute, University of
Pennsylvania, Philadelphia, PA, USA; MRC Biostatistics Unit, Institute of Public Health, Cambridge, UK; CR-UK Department of
Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; Department of Cardiovascular
Sciences, University of Leicester, Glenfield Hospital, Leicester, UK; MRC Epidemiology Unit, Institute of Metabolic Science,
Addenbrooke's Hospital, Cambridge, UK.

Received June 2, 2011; accepted July 25, 2011; Epub August 3, 2011; published August 30, 2011

Abstract: Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3
might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins
in the development of CAD in human populations is unclear.  We conducted a nested case-control study, with a mean follow-up
of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk
of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date.  After adjustment for
cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio:
0.98 (95% CI 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% CI 0.94-1.12) for IGFBP-3).  We examined
associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and
IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that
showed independent association with either circulating IGF-I or IGFBP-3 levels.  In an assessment of 31 SNPs spanning the
IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional
studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be
importantly involved in the aetiology of CAD in human populations. (IJMEG1106002).

Key words: Epidemiology, Genetics of cardiovascular disease, Risk factors, IGF1, IGFBP3

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Address all correspondence to:
Dr. Manjinder S. Sandhu
Department of Public Health and Primary Care
University of Cambridge, Strangeways Research Laboratory
Worts Causeway, Cambridge, CB1 8RN, UK.  
Tel: +44-(0)1223 740567, Fax: +44-(0)1223 740147
Email: ms23@sanger.ac.uk