Relationship Between Vitamin D Receptor Polymorphisms And The Efficacy Of RhGH Treatment In Children With Idiopathic Short Stature

Background:.Idiopathic short stature(ISS) comprises the overwhelming majority of the subjects evaluated for short stature in pediatric endocrine clinics, accounting for 60% ~ 80%, and the efficacy of rh GH treatment having been a research focus is variable. The pathogenesis of ISS is a multifactorial regulation influencing by systemic and local hormones, nutritional factors, lifestyle and genetic factors that are not yet fully clarified. The heritability of height accounted for 75%. A large of reports had prove that the growth hormone(GH)- insulin like growth factor(IGF)-I axis is one of the main actors in the growth process, playing an important role in the pathogenesis of ISS. Some studies suggests that ISS are related with gene mutation, gene single nucleotide polymorphisms and the related genetic abourt epiphyseal growth plate maturation. And there being some other growth-related genes closely linked with physiological processes,but not related to GH- IGF axis directly. With the development of molecular biology and detection methods, the gene mutations associated growth failure, gene polymorphisms and epigenetic research has become a hot spot. Recent studies have found that polymorphisms in the VDR promoter are associated with ISS in Korean children, whereas there is no such reports in our country, also have no the relationship between polymorphism of vitamin D receptor and the efficacy of recombinant human growth hormone(rh GH) treatment.Objective: To determine whether polymorphisms in the VDR promoter has relationship with ISS in Chinese children and whether the polymorphisms in the VDR promoter of Chinese children with ISS correlate with the efficacy of rh GH treatment, to provide a preliminary basis for clinical individual therapy.Methods: Ninety-five prepubertal children with ISS(ISS cases) and Ninety-five healthy age- and gender-matched children(controls) were enrolled. Genomic DNA was extracted from whold blood, then two single nucleotide polymorphisms(SNPs) in the VDR promoter(rs11568820 at the Cdx-2 binding site upstream of exon 1e and rs4516035 at-1012 upstream of exon 1a) were selected for typing bya 3730 XL DNA Analyzer. ISS cases should be treated with rh GH [0.35-0.42 mg/(kg?w)] more than six months. Growth velocity, the standard deviation score(SDS) of height for chronological age(Ht SDSca), height SDS for bone age(Ht SDSba), predicted adult height(PAH) and serum levels of IGF-1 and IGFBP-3 of the ISS patients were determined before and after 6 months of rh GH treatment.Results: 1.There were no significant differences in genotype frequencies between the ISS cases and controls. 2.After 6 months of treatment with rh GH, the growth velocity of the A/G genotype at the Cdx-2 binding site SNP locus was significantly higher than that of the G/G genotype, and the levels of IGF-1 and IGFBP-3 increased in the treated compared with the untreated group, but these changes were independent of the VDR promoter genotype. 3.rh GH therapy have little influence on bone age, thyroid function, blood glucose, liver function.Conlusions: 1.VDR promoter polymorphisms(rs11568820 and rs4516035)may not account for the pathogenesis of ISS in Chinese children. 2.The polymorphisms in the VDR promoter of Chinese children with ISS correlate with the efficacy of rh GH treatment, the A/G genotype has a significantly higher growth velocity than the G/G genotype. 3.The treatment of rh GH is basic safety.