Genetic and nongenetic factors associated with variation of plasma levels of insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in healthy premenopausal women

Circulating levels of insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein 3 (IGFBP-3) vary considerably between normal individuals, Recent epidemiological studies have provided evidence that th ese levels are predictive of risk of several common cancers. To evaluate po ssible sources of variation of the levels of circulating IGF-I and IGFBP-3 in females, we studied specific candidate genetic and nongenetic factors in 311 nulliparous, premenopausal Caucasian women, 17-35 years of age. Women who used oral contraceptives (OC) had reduced levels of IGF-I (269 versus 3 01 ng/ml; P = 0.001 adjusted for age) and increased levels of IGFBP-3 (4213 versus 4009 ng/ml; P = 0.002, adjusted for age) compared with nonusers. Th e ratio of IGF-I:IGFBP-3 was associated with the dose of estrogen contained in the OC (P-trend = 0.006, adjusted for age). We identified a novel singl e bp polymorphism in the promoter region of the gene encoding IGFBP-3. This polymorphism was related to the level of IGFBP-3 in the circulation. Mean IGFBP-3 levels were 4390, 4130, and 3840 ng/ml for the AA, AC, and CC genot ypes, respectively (P-trend = 0.006, adjusted for age and OC use). We obser ved no effect of a recently described polymorphism in the promoter region o f the gene encoding IGF-I on the plasma IGF-I level, but there was evidence for a modifying effect of this locus on the influence of OC on the IGF-I l evel. Our results support the view that circulating IGF-I levels and IGFBP- 3 levels are complex traits and are influenced by a number of interacting g enetic and nongenetic factors.