Genetic and epigenetic variability in the gene for IGFBP-3 (IGFBP3): Correlation with serum IGFBP-3 levels and growth in short children born small for gestational age
Context: IGF-I and IGFBP-3 play a central role in fetal and postnatal growth and levels are low in short SGA children. The -202 A/C and -185 C/T SNPs are located near elements involved in directing IGFBP3 promoter activity and expression. Changes in promoter CpG methylation status affect transcription factor binding and transcriptional activation of IGFBP3 in vitro. Objective: To assess the relationship between IGFBP3 promoter SNPs, IGFBP-3 levels, spontaneous growth and growth response to GH treatment in short prepubertal SGA children. To assess promoter methylation status in a subgroup of short SGA subjects and controls. Patients: 292 Short prepubertal SGA children, 39 short young SGA adults and 85 young adults with normal stature. Intervention: Short prepubertal SGA children received GH 1 mg/m2/day. Outcome measures: Fasting levels of IGF-I and IGFBP-3, baseline and delta height SDS. Results: At baseline, IGFBP-3 levels were highest in SGA children with -202 AA genotype and lower in children with 1 or 2 copies of the C-allele (P < 0.001). Children with C-202/C-185haplotype, compared to children with A-202/C-185haplotype, had lower IGFBP-3 levels (P = 0.003) and were shorter (P = 0.03). During GH treatment, children with C-202/C-185haplotype showed a significantly greater increase in IGFBP-3 SDS and in height SDS than children with A-202/C-185haplotype, resulting in similar IGFBP-3 levels and similar height SDS after 12 months of GH treatment. CpG methylation patterns showed a trend towards more methylation of CpGs involved in transcription factor binding in short young SGA adults compared to controls. Conclusion: Polymorphic variation in the IGFBP3 promoter region is correlated with IGFBP-3 levels, spontaneous growth and response to GH treatment in short SGA children.