The Association Between Matrix Metalloproteinase-1, -2, -3, -9, and -12 Gene Polymorphisms and Atrial Fibrillation

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia associated with significant morbidity and mortality. Structural remodeling of the left atrium, particularly myocardial fibrosis, plays a key role in AF pathogenesis. Matrix metalloproteinases (MMPs) are critical regulators of extracellular matrix remodeling and may contribute to atrial fibrosis through genetic variation. This case-control study included 179 patients with AF and 56 controls. Eight polymorphisms across five MMP genes (MMP1, MMP2, MMP3, MMP9, and MMP12) were analyzed using PCR-based methods. Associations between single-nucleotide polymorphisms (SNPs), AF susceptibility, recurrence, haplotypes, and gene-gene interactions were assessed. The study population was ethnically homogeneous (Polish), minimizing population stratification bias. No significant differences in allele frequencies were observed between AF and control groups in univariate analysis. However, multivariable logistic regression revealed significant associations for MMP1 rs1799750 and MMP2 rs243864 under recessive inheritance models. Haplotype analysis demonstrated a significant global association with AF (p = 0.027), with specific haplotypes showing markedly increased risk. Multifactor dimensionality reduction identified significant gene-gene interactions, particularly involving SNPs in MMP1, MMP2, MMP3, and MMP12. These findings support a polygenic model of AF susceptibility involving extracellular matrix remodeling pathways and highlight the importance of multi-locus genetic analyses.