Genetic aspects of growth hormone deficiency in children: the role of VDR polymorphisms

Background. In recent years, growing attention has been focused on the role of vitamin D and its receptor (VDR) gene in regulating not only calcium-phosphorus metabolism but also the differentiation of somatotroph cells in the pituitary gland, synthesis of insulin-like growth factor 1 (IGF-1) in the liver, and the maintenance of normal cartilage remodeling. The VDR gene contains several polymorphisms, among which the most studied ones are BsmI (rs1544410), TaqI (rs731236), and ApaI (rs7975232), loca­ted in the 3’ untranslated region. Although these polymorphisms do not alter the amino acid sequence of the receptor, they may influen­ce mRNA stability and VDR expression, thereby modula­ting the biological response to vitamin D. The purpose of the study was to assess the impact of combined VDR gene polymorphisms (BsmI, TaqI, ApaI) on hormonal, metabolic, and biochemical parameters in children with growth hormone (GH) deficiency. Materials and methods. Genotyping was performed in 42 children with confirmed GH deficiency. The VDR gene polymorphisms BsmI (rs1544410), TaqI (rs731236), and ApaI (rs7975232) were identified using polymerase chain reaction followed by restriction fragment length polymorphism analysis and agarose gel electrophoresis. Results. The most common genotype combination across the three loci was heterozygous (G/A + T/C + A/C) — 55.56 %, while the rarest was the homozygous pathological variant (A/A + C/C + A/A) — 16.66 %. Children with the homozygous pathological genotype had the lowest basal and stimulated GH levels, indicating more pronounced hormonal deficiency. Serum 25(OH)D levels were reduced in all groups; however, children with the normal genotype had vitamin D deficiency, while those with heterozygous and homozygous variants exhibited its insufficiency. Correlation analysis revealed significant relationships between vitamin D levels, IGF-1, GH, body mass index, bone age, and height standard deviation score. Notably, a strong inverse correlation was observed between IGF-1 and height standard deviation score in children with the pathological homozygous genotype. Blood biochemical parameters (calcium, phosphorus, creatinine, urea, cholesterol) showed no significant differences between genotypes and remained within normal limits. Regression analysis confirmed a significant influence of bone age on IGF-1 and stimulated GH levels, as well as an association between IGF-1 and stimulated GH. Conclusions. The analysis of combined genotypes of VDR and COL1A1 polymorphisms showed that the most prevalent combination in children with GH deficiency was GATCACGG (38.12 %). These findings underscore the critical role of genetic factors in the pathogenesis of GH deficiency and highlight the potential for developing personalized approaches to diagnosis, prognosis, and treatment of this condition.