BACKGROUND: Circulating levels of insulin-like growth factor I (IGF-I) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-I and IGFBP-3 in studies of adult twins. METHODS: We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-I and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNP) were genotyped in >5,500 Caucasian men and 5,500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium. RESULTS: After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-I (P < 2.1 × 10(-4)); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R(2) = 0.62% of the variation in circulating IGF-I and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-I or IGFBP-3 and risk of prostate or breast cancers. CONCLUSION: Common genetic variation in the IGF1 and SSTR5 genes seems to influence circulating IGF-I levels, and variation in IGFBP3 and IGFALS seems to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-I and IGFBP-3 in Caucasian men and women. IMPACT: Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes.

Original publication

DOI

10.1158/1055-9965.EPI-10-0507

Type

Journal article

Journal

Cancer Epidemiol Biomarkers Prev

Publication Date

11/2010

Volume

19

Pages

2877 - 2887

Keywords

Aged, Biomarkers, Tumor, Breast Neoplasms, Carrier Proteins, Cohort Studies, Enzyme-Linked Immunosorbent Assay, Female, Genetic Predisposition to Disease, Genotype, Glycoproteins, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Male, Middle Aged, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Receptors, Somatostatin, Risk Factors, Signal Transduction