​The association of GNAS defects with pro-inflammatory adipokine levels in pseudohypoparathyroidism type 1.

PURPOSE: Pseudohypoparathyroidism type 1 (PHP1), caused by GNAS defects, is associated with metabolic syndrome components like obesity and insulin resistance, potentially involving adipokine dysregulation. This study characterized serum adipokine profiles in PHP1 and elucidated the independent and interactive effects of GNAS defects and obesity. METHODS: This single-center, cross-sectional study included 60 PHP1 patients with molecularly confirmed GNAS defects (epigenetic or genetic). Controls (n = 60) were matched for body mass index (BMI), age, and sex. Serum adipokines were measured using multiplex enzyme-linked immunosorbent assay. Generalized linear models assessed independent/joint effects of GNAS defects and obesity on adipokines, adjusting for confounders. RESULTS: Overweight/obesity (OW/OB) prevalence was 58.3% among these PHP1 patients, significantly higher in PHP1A (90.9%, n = 11) vs. PHP1B (51.0%, n = 49; P = 0.037). Compared to controls, PHP1 patients exhibited significantly higher monocyte chemoattractant protein-1 (MCP-1) (P = 0.001), resistin (P = 0.001), chemerin (P < 0.001), adipsin (P = 0.007), and advanced glycation end-product receptor (AGER) (P = 0.014), but lower interleukin-8 (IL-8) (P < 0.001). After adjusting for age, sex, OW/OB, calcium, and parathyroid hormone, GNAS defects still independently increased resistin (mean difference [MD] = 0.76 ng/mL, P = 0.034), chemerin (geometric mean ratio [GMR] = 1.15, P = 0.008), and MCP-1 (GMR = 1.21, P = 0.043), but decreased IL-8 (GMR = 0.50, P = 0.004). Within PHP1 patients, resistin was higher in OW/OB individuals vs. non-OW/OB individuals (MD = 1.22 ng/mL, P = 0.005). Interaction analysis showed additive independent effects of GNAS defects and obesity on resistin level (P interaction=0.446). CONCLUSION: GNAS defects are associated with aberrant pro-inflammatory adipokine secretion (resistin, chemerin, MCP-1, IL-8) in PHP1 patients independently of obesity. Obesity appears to amplify metabolic dysregulation, particularly reflected by increased resistin levels. These findings support the importance of early metabolic risk assessment and potential targeted interventions in PHP1.