Elucidating Genetic Drivers of Chronic Inflammation in Obesity

Background/Objectives: Obesity is characterized by chronic low-grade inflammation, which plays a central role in the development of its metabolic complications. The genetic factors influencing this inflammatory phenotype remain incompletely understood. This study aimed to analyze the associations of functional polymorphisms in genes involved in extracellular matrix remodeling (MMP2, MMP9, MMP12, COL1A1), metabolism (MTHFR, CYP3A5), and vascular regulation (NOS3, AGTR1) with plasma cytokine profiles and to identify inflammatory subphenotypes in patients with obesity. Methods: The study included 127 individuals, comprising 73 patients with excess body weight (body mass index, BMI ≥ 25 kg/m²) and 54 individuals with normal weight (BMI 18.5-24.9 kg/m²). Genotyping of selected polymorphisms was performed using real-time PCR. Plasma concentrations of 47 cytokines and chemokines were measured by multiplex immunoassay. Results: Nominally significant associations between genetic variants and cytokine levels were identified. Polymorphisms COL1A1 rs1107946 (CA genotype) and MMP9 rs17576 (AG genotype) were associated with a favorable inflammatory profile (decreased IL-6 and increased IL-10, respectively). In contrast, the AGTR1 rs5186 (AC genotipe) variant was associated with elevated TNF-α, IP-10/CXCL10, while the MTHFR rs1801131 (AC genotipe) variant was linked to increased MIP-1β/CCL4, both reflecting a pro-inflammatory shift. Complex, pleiotropic associations were observed for MMP2 rs243865 (elevated IL-7 and Fractalkine/CX3CL1) and NOS3 rs1799983 (elevated MCP-1/CCL2 and Eotaxin/CCL11). Cluster analysis revealed distinct patient subpopulations with differing inflammatory signatures. In one well-defined subgroup, an exploratory model (test R² = 0.537) identified IL-8, IL-15, and albumin as candidate biomarkers predictive of BMI. Conclusions: The study identifies candidate genetic polymorphisms and inflammatory biomarkers associated with distinct patterns of systemic inflammation in obesity. These hypothesis-generating findings underscore the phenotypic heterogeneity of obesity and provide a basis for further research into the stratification of patients by the risk of developing metabolic complications.