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.

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.

• Authors: Fredrick R Schumacher, Iona Cheng, Matthew L Freedman, Lorelei Mucci, Naomi E Allen, Michael N Pollak, Richard B Hayes, Daniel O Stram, Federico Canzian, Brian E Henderson, David J Hunter, Jarmo Virtamo, Jonas Manjer, J Michael Gaziano, Laurence N Kolonel, Anne Tjønneland, Demetrius Albanes, Eugenia E Calle, Edward Giovannucci, E David Crawford, Christopher A Haiman, Peter Kraft, Walter C Willett, Michael J Thun, Loïc Le Marchand, Rudolf Kaaks, Heather Spencer Feigelson, H Bas Bueno-de-Mesquita, Domenico Palli, Elio Riboli, Eiliv Lund, Pilar Amiano, Gerald Andriole, Alison M Dunning, Dimitrios Trichopoulos, Meir J Stampfer, Timothy J Key, Jing Ma
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 19 Issue 15 Pg. 3089-101 (Aug 01 2010) ISSN: 1460-2083 [Electronic] England
• PMID: 20484221 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Insulin-Like Growth Factor Binding Protein 1
• Insulin-Like Growth Factor Binding Protein 3
• Insulin-Like Growth Factor I

Topics

• Aged
• Breast Neoplasms (blood, genetics)
• Cohort Studies
• Female
• Genetic Predisposition to Disease
• Genetic Variation
• Humans
• Insulin-Like Growth Factor Binding Protein 1 (genetics)
• Insulin-Like Growth Factor Binding Protein 3 (blood, genetics)
• Insulin-Like Growth Factor I (genetics, metabolism)
• Linkage Disequilibrium (genetics)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide (genetics)
• Prostatic Neoplasms (blood, genetics)
• Risk Factors
• White People (genetics)