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

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/m2 (P trend<0.05). Similarly, in CART analyses, compared with individuals having BMI<24kg/m2, 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/m2 and DISI<9.85 mg/day (OR = 1.95, 95%CI: 1.03-3.69), and also for those with BMI≥24kg/m2 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/m2, and DISI<9.85 mg/day on increased BC risk, particularly among postmenopausal women.