Eighteen Insulin-like Growth Factor (IGF) pathway genes, circulating levels of IGF-1 and its binding protein (IGFBP-3), and risk of prostate and breast cancer

Background: Circulating levels of insulin-like growth factor I (IGF-1) 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-1 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-1 and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNPs) were genotyped in over 5500 Caucasian men and 5500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium (BPC3). Results: After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-1 (p<2.1x10 -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-1 and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-1 or IGFBP-3 and risk of prostate or breast cancers. Conclusion: Common genetic variation in the IGF1 and SSTR5 genes appears to influence circulating IGF-1 levels, and variation in IGFBP3 and IGFALS appears to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-1 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. Inter-laboratory reproducibility was assessed with 30 SNPs on 94 samples from the Coriell Biorepository (Camden, NJ); the concordance rates were greater than 99% for Taqman assay, and 99.5% for the Illumina OPA assay. The internal quality of each genotyping center was assessed by typing 5-10% blinded samples in duplicate or greater, and the concordance ranged from 97.2 to 99.9%. Each allele was weighted by its regression coefficient from the multivariable model of the biomarker on significant SNPs (see previous paragraph). We then examined the associations between the IGF-1 and IGFBP-3 scores and cancer incidence (breast cancer among women and prostate cancer among men), using a logistic regression model. This model included main effects for each of the two scores, as well as main effects for study and age (in five-year age categories). In summary, our study suggests that common genetic variation in the IGF1 and SSTR5 genes affects circulating IGF-1 levels, and that the same may be true for variation in the IGFALS gene. In addition, common genetic variation in the IGFBP3 and IGFALS genes may influence the concentration of circulating IGFBP-3. Common genetic variation in the other 14 genes in the IGF signaling pathway that we studied had no important impact on circulating IGF-1 or IGFBP-3 levels. Common genetic variation in the pathway accounts for only a small percentage of circulating levels of these biomarkers among Caucasians (0.62% for IGF-1 and 3.9% for IGFBP-3). Other factors such as rare variants in these genes, structural changes in these genes, genetic variation outside of the regions we studied, and gene-environmental interactions, along with lifestyle and environmental exposures, may make their own contributions to IGF-1 and IGFBP-3 variation in population.