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

Background: Hypoadiponectinemia, a metabolic hallmark of obesity, is common in polycystic ovary syndrome (PCOS) yet the association of variants in the ADIPOQ gene with obesity in PCOS remains uncertain. To investigate whether ADIPOQ 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. Methodology: In 324 Tunisian women with PCOS, classified as obese or non-obese by WHO criteria, serum adiponectin was measured, and nine ADIPOQ 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. Results: 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, p = 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. Conclusions:ADIPOQ 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.