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Genetic Determinants of Circulating Insulin-Like Growth Factor (IGF)-I, IGF Binding Protein (BP)-1, and IGFBP-3 Levels in a Multiethnic Population

Department of Epidemiology and Biostatistics and Institute of Human Genetics (I.C.), University of California, San Francisco, San Francisco, California 94143-0794; Department of Preventive Medicine (K.D.H., C.A.H., B.E.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90089; Department of Medical Oncology (M.L.F.), Dana-Farber Cancer Institute, Boston, Massachusetts 02215; Program in Medical and Population Genetics (M.L.F.), Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142; and Epidemiology Program (L.N.K., L.L.M.), Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 96813

Address all correspondence and requests for reprints to: Iona Cheng, Department of Epidemiology and Biostatistics, University of California, San Francisco, California 94143-0794. E-mail: chengi{at}humgen.ucsf.edu.

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.