Genetic determinants of circulating insulin-like growth factor (IGF)-I, IGF binding protein (BP)-1, and IGFBP-3 levels in a multiethnic population

Context: Both circulating levels and genetic variation of IGFs have been associated with cancer risk, yet the relationship between the two is not well understood. Objective: To investigate whether common genetic variation in IGF1, IGF binding protein 1 (IGFBP1), and IGFBP3 influences circulating levels of IGF-I, IGFBP-1, and IGFBP-3, we conducted a cross-sectional study of African-American, Native Hawaiian, Japanese-American, Latino, and white men and women in the Multiethnic Cohort. Design: Plasma levels of IGF-I, IGFBP- 1, and IGBFP-3 were measured by ELISA in a random sample of 837 Multiethnic Cohort participants. Previously identified tag single nucleotide polymorphisms ( SNPs) for IGF1 (29 tag SNPs) and IGFBP1/ IGFBP3 ( 23 tag SNPs) were genotyped among the 837 participants. Analysis of covariance was conducted to test for differences in mean IGF-I, IGFBP- 1, and IGFBP- 3 levels across respective IGF1, IGFBP1, and IGFBP3 genotypes, adjusting for previously identified dietary and lifestyle correlates. Results: Five highly correlated IGFBP3 SNPs (rs3110697, rs2854747, rs2854746, rs2854744, and rs2132570) demonstrated strongly significant associations with IGFBP- 3 levels when conservatively adjusted for multiple hypothesis testing (Bonferroni adjusted P trends = 7.75 X 10(-8) to 1.44 X 10(-5)). Patterns of associations were consistent across the five racial/ethnic groups. Conclusion: In summary, our study suggests that common genetic variation in IGFBP3 influences circulating levels of IGFBP- 3 among African-Americans, Native Hawaiians, Japanese-Americans, Latinos, and whites.