Genetic Insights into Breast Cancer in Northeastern Mexico: Unveiling Gene–Environment Interactions and Their Links to Obesity and Metabolic Diseases

<b>Background:</b> Breast cancer (BC), one of the most common cancers, has increased in Mexico during the past decade, along with other chronic and metabolic diseases. <b>Methods:</b> Herein, we analyzed 121 SNPs (85 SNPs related to BC and/or glucose-associated metabolic pathways and 36 SNP classified as ancestry markers) in 92 confirmed BC cases and 126 unaffected BC women from Northeastern Mexico. The relationship of these 121 SNPs with BC, considering BMI, menopause status, and age as cofactors, was explored using a gene-environment (G × E) interaction multi-locus model. <b>Results:</b> Twelve gene variants were significantly associated with BC: three located in exome (rs3856806 <i>PPARG</i>, rs12792229 <i>MMP8</i>, and rs5218 <i>KCNJ11-ABCC8</i>), and nine in non-coding regions, which are involved in accelerated decay of the mRNA transcripts, regulatory regions, and flanking regions (rs3917542 <i>PON1</i>; rs3750804 and rs3750805 <i>TCF7L2</i>; rs1121980 and rs3751812 <i>FTO</i>; rs12946618 <i>RPTOR</i>; rs2833483 <i>SCAF4</i>; rs11652805 <i>AMZ2P1-GNA13</i>; and rs1800955 <i>SCT-DEAF1-DRD4)</i>. <b>Conclusions:</b> This study identified an association between BC and menopause, age (above 45), obesity, and overweight status with gene variants implicated in diabetes mellitus, obesity, insulin resistance, inflammation, and remodeling of the extracellular matrix.