Human Molecular Genetics Advance Access originally published online on February 4, 2008
Human Molecular Genetics 2008 17(10):1457-1464; doi:10.1093/hmg/ddn034
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Identification of genetic variants that influence circulating IGF1 levels: a targeted search strategy
1 Breakthrough Breast Cancer Research Centre 2 Gene Function and Regulation, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK 3 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK 4 Mutation Detection Facility, Cancer Research UK, St James’s University Hospital, Leeds LS9 7TF, UK 5 University Department of Clinical Science at North Bristol, Southmead Hospital, Bristol BS10 5NB, UK 6 Academic Oncology Unit, Guy’s Hospital, London SE1 9RT, UK 7 Cancer Research UK Epidemiology and Genetics Group, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
* To whom correspondence should be addressed: Tel: +44 2071535332; Fax: +44 2078783858; Email: claire.palles{at}icr.ac.uk
Received December 11, 2007; Accepted January 30, 2008
An important class of genetic variants that affect disease susceptibility may lie within regulatory elements that influence gene expression. Regulatory sequences are difficult to identify and may be distant from the genes they regulate, but many lie within evolutionarily conserved regions (ECRs). We used comparative genomics to identify 12 ECRs up to 75 kb 5' to and within introns of IGF1. These were screened by high-resolution melting curve analysis, and 18 single-nucleotide polymorphisms (SNPs) were identified, including five novel variants. We analysed two large population-based series of healthy women to test the nine SNPs with minor allele frequency (MAF) >1% within ECRs. Three of the nine SNPs within ECRs (rs35455143, rs35765817 and rs3839984) were significantly associated with circulating IGF1 levels in a multivariate analysis (P 
0.02 for each SNP, overall significance P < 0.001). All three are uncommon SNPs (MAF 10%) that lie >70 kb 5' of IGF1. Two (rs35455143 and rs35765817) are in strong LD with each other and appear to have opposite effects on circulating IGF1. Our results on a subset of other SNPs in or near IGF1 were consistent with previously reported associations with IGF1 levels, although only one (rs35767: P = 0.05) was statistically significant. We believe that this is the first systematic study of an association between a phenotype and SNPs within ECRs extending over a large region adjacent to a gene. Targeting ECRs appears to be a useful strategy for identifying a subset of potentially functional non-coding regulatory SNPs.