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 †On behalf of the NCI Breast & Prostate Cancer Cohort Consortium

The insulin-like growth factor pathway (IGF) has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging 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 fourteen IGF1 single-nucleotide polymorphisms (SNPs) and sixteen IGFBP1/IGFBP3 SNPs to capture common (MAF ≥5%) variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N=5,684) across genotypes and the association with PCa risk (6,012 PCa cases/6,641 controls). We present two-sided statistical tests and correct for multiple comparisons. A nonsynonymous IGFBP3 SNP in exon1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (Padj=8.8x10) after adjusting for the previously established IGFBP3 promoter polymorphism A202C (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 8.7x10. IGF-I levels were significantly associated with PCa risk (Ptrend=0.02) with a 21% increase of PCa risk comparing 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.