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- Title
A comprehensive analysis of common IGF1, IGFBP1 and IGFBP3 genetic variation with prospective IGF-I and IGFBP-3 blood levels and prostate cancer risk among Caucasians.
- Authors
Schumacher, Fredrick R; Cheng, Iona; Freedman, Matthew L; Mucci, Lorelei; Allen, Naomi E; Pollak, Michael N; Hayes, Richard B; Stram, Daniel O; Canzian, Federico; Henderson, Brian E; Hunter, David J; Virtamo, Jarmo; Manjer, Jonas; Gaziano, J Michael; Kolonel, Laurence N; Tjønneland, Anne; Albanes, Demetrius; Calle, Eugenia E; Giovannucci, Edward; Crawford, E David; Haiman, Christopher A; Kraft, Peter; Willett, Walter C; Thun, Michael J; Le Marchand, Loïc; Kaaks, Rudolf; Feigelson, Heather Spencer; Bueno-de-Mesquita, H Bas; Palli, Domenico; Riboli, Elio; Lund, Eiliv; Amiano, Pilar; Andriole, Gerald; Dunning, Alison M; Trichopoulos, Dimitrios; Stampfer, Meir J; Key, Timothy J; Ma, Jing
- Abstract
The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1, IGF binding protein (BP) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1/IGFBP3 SNPs to capture common [minor allele frequency (MAF) >or= 5%] variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N = 5684) across genotypes and the association with PCa risk (6012 PCa cases/6641 controls). We present two-sided statistical tests and correct for multiple comparisons. A non-synonymous IGFBP3 SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (P(adj) = 8.8 x 10(-43)) after adjusting for the previously established IGFBP3 promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. For IGF1 SNP rs4764695, the risk estimates among heterozygotes was 1.01 (99% CI: 0.90-1.14) and 1.20 (99% CI: 1.06-1.37) for variant homozygotes with overall PCa risk. The corrected allelic P-value was 8.7 x 10(-3). IGF-I levels were significantly associated with PCa risk (P(trend) = 0.02) with a 21% increase of PCa risk when compared with the highest quartile to the lowest quartile. We have identified SNPs significantly associated with IGFBP-3 blood levels, but none of these alter PCa risk; however, a novel IGF1 SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians.
- Publication
Human molecular genetics, 2010, Vol 19, Issue 15, p3089
- ISSN
1460-2083
- Publication type
Journal Article
- DOI
10.1093/hmg/ddq210