Genetic variation and circulating levels of IGF-I and IGFBP-3 in relation to risk of proliferative benign breast disease.

Insulin-like growth factor-I (IGF-I) and its major binding protein IGFBP-3 have been implicated in breast carcinogenesis. We examined the associations between genetic variants and circulating levels of IGF-I and IGFBP-3 with proliferative benign breast disease (BBD), a marker of increased breast cancer risk, in the Nurses' Health Study II (NHSII). Participants were 359 pathology-confirmed proliferative BBD cases and 359 matched controls. Circulating IGF-I and IGFBP-3 levels were measured in blood samples collected between 1996 and 1999. Thirty single nucleotide polymorphisms (SNPs) in IGF-I, IGFBP-1, and IGFBP-3 genes were selected using a haplotype tagging approach and genotyped in cases and controls. Circulating IGF-I levels were not associated with proliferative BBD risk. Higher circulating IGFBP-3 levels were significantly associated with increased risk of proliferative BBD (highest vs. lowest quartile odds ratio (OR) [95% confidence interval (CI)], 1.70 (1.06-2.72); p-trend = 0.03). The minor alleles of 2 IGFBP-3 SNPs were associated with lower proliferative BBD risk (homozygous variant vs. homozygous wild-type OR (95% CI): rs3110697: 0.6 (0.4-0.9), p-trend = 0.02; rs2132570: 0.2 (0.1-0.6), p-trend = 0.02). Three other IGFBP-3 SNPs (rs2854744, rs2960436 and rs2854746) were significantly associated with circulating IGFBP-3 levels (p < 0.01). Although these SNPs were not significantly associated with proliferative BBD risk, there was suggestive evidence that the alleles associated with higher circulating IGFBP-3 levels were also associated with higher risk of proliferative BBD. These results suggest that genetic variants and circulating levels of IGFBP-3 may play a role in the early stage of breast carcinogenesis.