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Human Molecular Genetics Advance Access originally published online on November 23, 2005
Human Molecular Genetics 2006 15(1):1-10; doi:10.1093/hmg/ddi398
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer

Ali Al-Zahrani1,{dagger},{ddagger}, Manjinder S. Sandhu2,{dagger}, Robert N. Luben3, Deborah Thompson4, Caroline Baynes1, Karen A. Pooley1, Craig Luccarini1, Hannah Munday1, Barbara Perkins1, Paula Smith4, Paul D.P. Pharoah1, Nicholas J. Wareham5, Douglas F. Easton4, Bruce A.J. Ponder1 and Alison M. Dunning1,*

1CR-UK Department of Oncology, 2Department of Public Health and Primary Care, 3EPIC, 4CR-UK Genetic Epidemiology Unit and 5MRC Epidemiology Unit, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK

* To whom correspondence should be addressed. Tel: +44 1223740683; Fax: +44 1223740147; Email: alisond{at}srl.cam.ac.uk

Received September 1, 2005; Accepted October 14, 2004

Experimental and observational studies in humans and animals suggest that insulin-like growth factor 1 (IGF1) and its principal binding protein, IGFBP3, may influence breast cancer susceptibility. We have examined the association of nine and four single nucleotide polymorphisms (SNPs) in the IGF1 gene and in the IGFBP3 genes, respectively, with circulating levels of their gene products in a population-based study of 600 middle-aged men and women, and in a breast cancer case–control study, comprised 4647 cases and 4564 controls. All study participants are from the East Anglian region of UK. SNPs were specifically chosen to tag all other known SNPs in each gene. Several SNPs in each gene are associated both with circulating levels of their respective proteins and with risk of breast cancer. In particular, the c allele of IGF1 SNPrs1520220 is associated with increased circulating IGF1 (r2=2.1%, P-trend=0.003) in females and an increased risk of breast cancer: odds ratio (OR) (cc/gg)=1.41; 95% confidence intervals (95% CI) 1.11–1.79, P-trend=0.03. The a allele of IGFBP3 SNP rs2854744 is associated with increased circulating IGFBP3 (r2=9.7%, P<10–9) and a decreased risk of breast cancer: OR (aa/cc)=0.87; 95% CI 0.77–0.99, P=0.03. Our data indicate that common variants in the IGF1 and IGFBP3 genes are associated with differences in circulating levels of IGF1 and IGFBP3 and with breast cancer risk. More specifically and consistent with experimental models, our data suggest that higher IGF1 levels may increase the risk of breast cancer but higher IGFBP3 levels may be protective.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

{ddagger} Present address: King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.


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