Genetic factors related to racial variation in plasma levels of insulin-like growth factor-1: implications for premenopausal breast cancer risk.

The oral contraceptive pill is associated with a modest increase in the risk of early-onset breast cancer in the general population, but it is possible that the risk is higher in certain subgroups of women. The relative risk of breast cancer associated with oral contraceptive use has been reported to be higher for African-American women than for white women. African-American women also have a higher incidence of premenopausal breast cancer than white women. Circulating levels of insulin-like growth factor-1 (IGF-I) vary between ethnic groups and are positively associated with the risk of premenopausal breast cancer. In general, the plasma level of IGF-I is lower in women who take oral contraceptives than in women who do not. In an attempt to explain the observed ethnic difference in IGF-I levels with oral contraceptive use, we sought to identify polymorphic variants of genes that are associated with IGF-I levels and estrogen metabolism. We measured IGF-I and IGFBP-3 plasma levels in 503 nulligravid women between the ages of 17 and 35. All women filled out a questionnaire that included information about ethnic background and oral contraceptive use. Samples of DNA were used to genotype the women for known polymorphic variants in the IGF1, AIB1, and CYP3A4 genes. Black women had significantly higher mean IGF-I levels than white women (330 ng/ml versus 284 ng/ml; P = 0.001, adjusted for age and oral contraceptive use). IGF-I levels were significantly suppressed by oral contraceptives in white women (301 ng/ml versus 267 ng/ml; P = 0.0003), but not in black women. Among oral contraceptive users, the IGF-I level was positively associated with the absence of the IGF1 19-repeat allele (338 ng/ml versus 265 ng/ml; P = 0.00007), with the presence of the CYP3A4 variant allele (320 ng/ml versus 269 ng/ml; P = 0.01), and with the presence of the AIB1 26-repeat allele (291 ng/ml versus 271; P = 0.08). After adjusting for genotypes, ethnic group was no longer a significant predictor of the IGF-I level. IGF-I levels are higher among black than white women. Polymorphic variants in the CYP3A4, IGF1, and AIB1 genes are associated with increases in the plasma levels of IGF-I among oral contraceptive users and the variant alleles are much more common in black women than in white women. The high incidence of premenopausal breast cancer among black women may be mediated through genetic modifiers of circulating levels of IGF-I.