Background: Results from several studies indicate that mammographic density, a strong risk factor for breast cancer, is greater in premenopausal women with higher circulating IGF-I levels. Both mammographic density and circulating IGF-I levels appear to be partly heritable traits. We hypothesized that in premenopausal women, IGF1 variants are associated with circulating IGF-I concentration, which in turn influences variation in breast density. Therefore, we examined the association of IGF1 polymorphisms with circulating IGF-I levels and mammographic density.
Methods: Percentage density, amounts of dense and non-dense (fat) tissue, IGF-I levels, and BMI were measured in 163 premenopausal women. Three CA repeat polymorphisms were genotyped, one each at the 5' and 3' ends of IGF1 and one in intron 2.
Results: The number of 19 alleles at the 5' polymorphism was associated with lower circulating levels of IGF-I (P = 0.02), whereas the number of 185 alleles at the 3' polymorphism was associated with higher percentage density (P = 0.03) and a smaller amount of non-dense tissue (P = 0.02). The strength of the effect of the 185 allele at 3' on percentage density was greatly reduced and statistical significance lost when BMI was included in regression models.
Conclusions: Our results suggest an association between the number of 185 alleles at 3' with percentage density. This association appears to be mediated by body composition and particularly body fat, as indicated by the association of 3' IGF1 genotype with non-dense (fat) tissue and the mediating effect of BMI on the association of 3' genotype with percentage density.