ADIPOQ Variants rs1501299 and rs3774261 and Hypoadiponectinemia in Obese Women with PCOS: Genetic and Metabolic Interactions

<b>Background:</b> Hypoadiponectinemia, a metabolic hallmark of obesity, is common in polycystic ovary syndrome (PCOS) yet the association of variants in the <i>ADIPOQ</i> gene with obesity in PCOS remains uncertain. To investigate whether <i>ADIPOQ</i> variants are associated with obesity in PCOS in relation to circulating adiponectin levels, and whether integrating genotypes, adiponectin, and a polygenic risk score (PRS) improves risk stratification. <b>Methodology:</b> In 324 Tunisian women with PCOS, classified as obese or non-obese by WHO criteria, serum adiponectin was measured, and nine <i>ADIPOQ</i> variants were genotyped using TaqMan assays. Associations with obesity were assessed using logistic regression, gene phenotype interaction analysis, and models incorporating a PRS; epistasis, QTL, and diplotypes were also evaluated. <b>Results:</b> Adiponectin levels were significantly lower in obese women and modestly predicted obesity (AUC = 0.605). Variants rs1501299 and rs3774261 were significantly associated with obesity under recessive models (OR up to 5.18, 95% CI [2.32-11.56], <i>p</i> = 7.14 × 10^-5). Risk genotypes and haplotypes correlated with reduced adiponectin and increased obesity risk, with adiponectin levels significantly associated with the genotype-obesity relationships. A combined model including adiponectin, the two variants, and PRS outperformed single predictors. <b>Conclusions:</b><i>ADIPOQ</i> rs1501299 and rs3774261 are associated with obesity in women with PCOS, with this association demonstrating a specific relationship with reduced adiponectin. Integrating genetic and biochemical markers improves metabolic risk profiling and supports personalized management.