© The Author 2006. Published by Oxford University Press.
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Common Genetic Variation in IGF1 and Prostate Cancer Risk in the Multiethnic Cohort
Affiliations of authors: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA (IC, DOS, MP, BEH); Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA (KLP, JH, DA, MLF); Department of Genetics (KLP, JH, DA, MLF), Medicine (KLP, DA, MLP), and Pediatrics (JH), Harvard Medical School, Boston, MA; Department of Molecular Biology (KLP, DA, MLP), Diabetes Unit (DA), and Hematology-Oncology (MLP), Massachusetts General Hospital, MA; Cancer Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI (LLM, LNK); Division of Genetics and Endocrinology, Children's Hospital and Department of Pediatrics, Boston, MA (JH)
Correspondence to: Matthew Freedman, MD, Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02139 (e-mail: freedman{at}broad.mit.edu).
Background: Insulin-like growth factor I (IGF-I) appears to play a role in prostate development and carcinogenesis. We investigated whether genetic variation at the IGF1 locus is associated with prostate cancer risk. Methods: We sequenced IGF1 exons in germline DNA from 95 men with advanced prostate cancer to identify missense variants. IGF1 linkage disequilibrium patterns and common haplotypes were characterized by genotyping 64 single-nucleotide polymorphisms (SNPs) spanning 156 kilobases in 349 control subjects. Associations between IGF1 haplotypes and genotypes were investigated among 2320 patients with prostate cancer and 2290 control subjects from the Multiethnic Cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression to determine the association between prostate cancer and IGF1 haplotypes and genotypes. We used permutation testing to correct for multiple hypothesis testing. All statistical tests were two-sided. Results: No IGF1 missense variants were observed. We identified four blocks of strong linkage disequilibrium and selected a subset of 29 tagging SNPs that could accurately predict both the common IGF1 haplotypes and the remaining SNPs. Haplotype analysis revealed nominally statistically significant associations with prostate cancer risk in each of the four haplotype blocks: haplotype 1B (OR = 1.21, 95% CI = 1.04 to 1.40), haplotype 2C (OR = 1.24, 95% CI = 1.06 to 1.44), haplotype 3C (OR = 1.25, 95% CI = 1.03 to 1.50), and haplotype 4D (OR = 1.19, 95% CI = 1.02 to 1.39). Two SNPs—rs7978742 (Ptrend = .002) and rs7965399 (Ptrend = .002)—were perfectly correlated (correlation coefficient = 1.0) with one another and also associated with prostate cancer risk. These two SNPs were strong proxies for haplotypes 1B, 2C, 3C, and 4D and could account for the haplotype findings. Permutation testing revealed that a similarly strong result would be observed by chance only 5.6% of the time. Conclusion: Inherited variation in IGF1 may play a role in the risk of prostate cancer.
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