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Background  Polymorphisms of  IGF-1  and  IGFBP-3  and environmental factors may work together to influence insulin-like growth factor (IGF) levels and thus breast cancer (BC) risk. However, very few studies have investigated high-order interactions among these variables.    Methods  A total of 277 newly diagnosed BC cases and 277 controls were recruited between October 2010 and July 2012. We collected each participant's demographic characteristics, dietary intake, and blood sample.  IGF-1 rs1520220  and  IGFBP-3 rs2854744  were then genotyped. A multi-analytic strategy combining unconditional logistic regression (ULR), generalized multifactor dimensionality reduction (GMDR), and classification and regression tree (CART) approaches was applied to systematically identify the interactions of the two single nucleotide polymorphisms (SNPs), body mass index (BMI), and daily intake of soy isoflavone (DISI) on BC susceptibility.    Results  In GMDR analyses, high-order interactions among BMI, DISI, and SNP  rs2854744  were identified among overall and postmenopausal women. We also found significant dosage effects on BC risk with an increasing number of exposure factors, namely carrying the  rs2854744  AA genotype, DISI <9.85 mg/day, and BMI ≥24 kg/m 2  ( P   trend <0.05). Similarly, in CART analyses, compared with individuals having BMI<24kg/m 2 , DISI<9.85 mg/day, and the  rs2854744  CC+CA genotype, BC risk increased significantly for those carrying the  rs2854744  AA genotype, with BMI<24 kg/m 2  and DISI<9.85 mg/day (OR = 1.95, 95%CI: 1.03–3.69), and also for those with BMI≥24kg/m 2  and DISI<9.85 mg/day (OR = 2.13, 95%CI: 1.00–4.51). Similar interaction effects were observed among postmenopausal women.    Conclusions  This study suggests high-order interactions of the  IGFBP-3 rs2854744 AA  genotype, BMI≥24kg/m 2 , and DISI<9.85 mg/day on increased BC risk, particularly among postmenopausal women.

Effects of High-Order Interactions among IGFBP-3 Genetic Polymorphisms, Body Mass Index and Soy Isoflavone Intake on Breast Cancer Susceptibility