Pavlova Nadezhda, Demin Sergey, Churnosov Mikhail, Reshetnikov Evgeny, Aristova Inna, Churnosova Maria, Ponomarenko Irina
Department of Medical Biological Disciplines, Belgorod State National Research University, 308015 Belgorod, Russia.
Biomedicines. 2022 Oct 18;10(10):2617. doi: 10.3390/biomedicines10102617.
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.
我们研究了肥胖对基质金属蛋白酶（MMP）基因多态性与乳腺癌（BC）风险之间关联的可能修饰作用。方法：根据体重指数（BMI）将1104名女性分为两组：BMI≥30（119例乳腺癌患者和190例对照）和BMI<30（239例乳腺癌患者和556例对照），对特意选择的（根据其在先前研究中与乳腺癌的关联）MMP1、2、3、8和9基因的10个单核苷酸多态性（SNP）进行基因分型。在每个研究的女性组（有/无肥胖）中进行逻辑回归关联分析。通过计算机生物信息学分析与乳腺癌相关的MMP多态性变体的功能注释。结果：我们观察到肥胖和非肥胖女性中MMP单核苷酸多态性在乳腺癌中的参与存在显著差异。多态性位点MMP9（c.836 A>G（rs17576）和c.1721 C>G（rs2250889））是肥胖女性患乳腺癌的保护因素（分别为等位基因模型中的OR 0.71和加性模型中的OR 0.55）。MMP2的TT基因型（c.-1306 C>T，rs243865）和MMP9的AA基因型（c.1331-163 G>A，rs3787268）决定了非肥胖女性患乳腺癌的易感性（分别为OR 0.31和OR 2.36）。我们通过计算机分析发现，与乳腺癌相关的多态性位点对脂肪组织中的基因表达有大量多向性影响：非肥胖女性中与乳腺癌风险相关的等位基因A-rs3787268与NEURL2、PLTP、RP3-337O18.9、SPATA25和ZSWIM1的低表达相关，而肥胖女性中与乳腺癌风险相关的等位基因A-rs17576与内脏和/或皮下脂肪中相同基因的高表达相关。结论：我们的研究表明，肥胖对绝经后女性中MMP基因与乳腺癌风险之间的关联具有显著的修饰作用。
