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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 theIGF1,IGFbinding protein (BP) 1, andIGFBP3genes 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 14IGF1SNPs and 16IGFBP1/IGFBP3SNPs to capture common [minor allele frequency (MAF) ≥ 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-synonymousIGFBP3SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (P  adj= 8.8 × 10−43) after adjusting for the previously establishedIGFBP3promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. ForIGF1SNP 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 allelicP-value was 8.7 × 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 novelIGF1SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians.

human molecular genetics

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               †