van der Kaay D C M, Hendriks A E J, Ester W A, Leunissen R W J, Willemsen R H, de Kort S W K, Paquette J R, Hokken-Koelega A C S, Deal C L
Endocrine Service, Sainte-Justine Hospital Research Center, University of Montreal, Pediatric Endocrinology, Montreal, Quebec, Canada.
Growth Horm IGF Res. 2009 Jun;19(3):198-205. doi: 10.1016/j.ghir.2008.08.010. Epub 2008 Oct 16.
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.
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.
292 Short prepubertal SGA children, 39 short young SGA adults and 85 young adults with normal stature.
Short prepubertal SGA children received GH 1mg/m(2)/day.
Fasting levels of IGF-I and IGFBP-3, baseline and delta height SDS.
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(-185) haplotype, compared to children with A(-202)/C(-185) haplotype, had lower IGFBP-3 levels (P=0.003) and were shorter (P=0.03). During GH treatment, children with C(-202)/C(-185) haplotype showed a significantly greater increase in IGFBP-3 SDS and in height SDS than children with A(-202)/C(-185) haplotype, 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.
Polymorphic variation in the IGFBP3 promoter region is correlated with IGFBP-3 levels, spontaneous growth and response to GH treatment in short SGA children.
胰岛素样生长因子-I（IGF-I）和胰岛素样生长因子结合蛋白-3（IGFBP-3）在胎儿期和出生后的生长中起核心作用，身材矮小的小于胎龄儿（SGA）儿童其水平较低。-202 A/C和-185 C/T单核苷酸多态性（SNP）位于参与指导IGFBP3启动子活性和表达的元件附近。启动子CpG甲基化状态的改变在体外会影响转录因子结合以及IGFBP3的转录激活。
评估青春期前矮小SGA儿童中IGFBP3启动子SNP、IGFBP-3水平、自然生长以及对生长激素（GH）治疗的生长反应之间的关系。评估矮小SGA受试者和对照组亚组中的启动子甲基化状态。
292名青春期前矮小SGA儿童、39名矮小的年轻SGA成年人以及85名身材正常的年轻成年人。
青春期前矮小SGA儿童接受1mg/m²/天的GH治疗。
空腹IGF-I和IGFBP-3水平、基线及身高标准差积分（SDS）变化值。
基线时，-202 AA基因型的SGA儿童中IGFBP-3水平最高，而携带1个或2个C等位基因拷贝儿童的该水平较低（P<0.001）。与携带A(-202)/C(-185)单倍型的儿童相比，携带C(-202)/C(-185)单倍型的儿童IGFBP-3水平较低（P=0.003）且身材更矮（P=0.03）。在GH治疗期间，携带C(-202)/C(-185)单倍型的儿童IGFBP-3 SDS和身高SDS的增加幅度显著大于携带A(-202)/C(-185)单倍型的儿童，导致GH治疗12个月后IGFBP-3水平和身高SDS相似。与对照组相比，矮小的年轻SGA成年人中，参与转录因子结合的CpG甲基化模式显示出CpG甲基化程度更高的趋势。
IGFBP3启动子区域的多态性变异与矮小SGA儿童的IGFBP-3水平、自然生长以及对GH治疗的反应相关。
