The lncOb rs10487505 polymorphism impairs insulin sensitivity and glucose tolerance in children and adolescents with obesity

Objective: Leptin plays a key role in the regulation of body weight and other endocrine systems. Recently, impairment of leptin gene transcription due to genetic variations in a long noncoding RNA (lncOb) has been described. This retrospective study aims to characterize the clinical and metabolic phenotype of children and adolescents with obesity who were homozygous for the lncOb rs10487505 leptin lowering allele. Methods: Enrolled children underwent an anthropometrical evaluation, biochemical assessment, and genotyping for lncOb rs10487505. Plasma leptin levels were assessed in 150 participants. A total of 434 patients were included and divided into two groups according to rs10487505 recessive inheritance (CC vs. GG/GC). Results: Children who were homozygous for the C allele showed higher fasting insulin (p = 0.01), homeostasis model assessment of insulin resistance (p = 0.01), lower whole-body insulin sensitivity index (p = 0.02), and lower disposition index (p = 0.03). Moreover, CC patients presented with a higher prevalence of prediabetes (9.3% vs. 3.4%, p = 0.04) and a 2.9-fold (95% CI: 1.1-7.9, p = 0.04) higher risk of prediabetes compared with G-carriers independently from confounders. Leptin plasma levels were significantly lower in the CC group (p = 0.002). Hormone levels correlated with BMI z score (r = 0.19, p = 0.04), fasting insulin (r = -0.34, p < 0.0001), homeostasis model assessment of insulin resistance (r = -0.33, p < 0.0001), and disposition index (r = 0.20, p = 0.04). Conclusions: The lncOb rs10487505 polymorphism affects leptin circulating levels, worsens insulin resistance, and heightens the risk of prediabetes in children and adolescents with obesity.