The association between inflammation and pubertal development: Insights from NHANES and Mendelian randomization...

Our research seeks to elucidate the interplay between inflammation and pubertal development using association and Mendelian randomization (MR) analyses, aiming to uncover the underlying potential causal relationship. Using data from the 2013 to 2016 and 2021 to 2023 National Health and Nutrition Examination Survey cycles, we assessed 3571 children and adolescents. To evaluate associations with pubertal status, logistic regression was performed for a panel of immune-inflammatory biomarkers: platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, systemic inflammation response index, systemic immune-inflammation index, and pan-immune-inflammation value. Bidirectional 2-sample MR analysis was conducted: genetic instruments for exposures were from a published genome-wide protein quantitative trait locus study (91 inflammatory proteins), and outcomes were precocious puberty (PP) summary statistics from the FinnGen consortium R11 database to infer causality. The median age of participants was 10.00 years, with 1838 males (51.47%) and 1733 females (48.53%). In association analysis, neutrophil-to-lymphocyte ratio showed a significant positive association with pubertal status across all models (fully adjusted: odds ratio [OR] = 1.198, 95% confidence interval [CI]: 1.095-1.311, P < .001). Systemic inflammation response index and systemic immune-inflammation index presented significant positive associations only in the fully adjusted model. Forward MR analysis suggested that genetically predicted higher levels of matrix metalloproteinase-10 (OR = 2.213, 95% CI: 1.218-4.024, P = .009) and osteoprotegerin (OR = 2.010, 95% CI: 1.082-3.734, P = .027) were associated with increased risk of PP, while higher tumor necrosis factor-β (TNF-β, OR = 0.678, 95% CI: 0.479-0.959, P = .028) decreased it. Reverse MR showed PP was positively associated with C-X-C motif chemokine ligand 1 (CXCL-1), fibroblast growth factor 5 (FGF-5), fibroblast growth factor 19 (FGF-19), interleukin-7, interleukin-15 receptor subunit alpha, neurturin, and negatively associated with tumor necrosis factor-related activation-induced cytokine. Inflammatory processes may contribute to PP pathogenesis via pathways influencing pubertal timing and progression, providing new insights into pubertal development mechanisms and a scientific basis for future interventions.