The Modifying Effect of Obesity on the Association of Matrix Metalloproteinase Gene Polymorphisms with Breast Cancer Risk
N. V. Pavlova, Sergey Demin, Mikhail Churnosov, Evgeny Reshetnikov, Inna Aristova, Maria Churnosova, Irina Ponomarenko
Abstract
Objective: We investigated the possible modifying effect of obesity on the association of matrix metalloproteinase (MMP) gene polymorphisms with breast cancer (BC) risk. Methods: A total of 1104 women divided into two groups according to their body mass index (BMI): BMI ≥ 30 (119 BC, and 190 control) and BMI < 30 (239 BC, and 556 control) were genotyped for specially selected (according to their association with BC in the previous study) 10 single-nucleotide polymorphisms (SNP) of MMP1, 2, 3, 8, and 9 genes. Logistic regression association analysis was performed in each studied group of women (with/without obesity). Functional annotation of BC-correlated MMP polymorphic variants was analyzed by in silico bioinformatics. Results: We observed significant differences in the involvement of MMP SNPs in BC in obese and non-obese women. Polymorphic loci MMP9 (c.836 A > G (rs17576) and c. 1721 C > G (rs2250889)) were BC-protective factors in obese women (OR 0.71, allelic model, and OR 0.55, additive model, respectively). Genotypes TT MMP2 (c.-1306 C > T,rs243865) and AA MMP9 (c. 1331-163 G > A,rs3787268) determined BC susceptibility in non-obese women (OR 0.31, and OR 2.36, respectively). We found in silico substantial multidirectional influences on gene expression in adipose tissue BC-related polymorphic loci: BC risk allele A-rs3787268 in non-obese women is associated with low expression NEURL2, PLTP, RP3-337O18.9, SPATA25, and ZSWIM1, whereas BC risk allele A-rs17576 in obese women is associated with high expression in the same genes in visceral and/or subcutaneous adipose. Conclusions: our study indicated that obesity has a significant modifying effect on the association of MMP genes with BC risk in postmenopausal women.