Deal C, Ma J, Wilkin F, Paquette J, Rozen F, Ge B, Hudson T, Stampfer M, Pollak M
Department of Pediatrics, Université de Montréal, Québec, Canada.
J Clin Endocrinol Metab. 2001 Mar;86(3):1274-80. doi: 10.1210/jcem.86.3.7280.
Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) is a major determinant of circulating levels of the IGFs and is clinically useful for the evaluation of GH deficiency and for predicting the response to GH treatment. Recent studies provide evidence that the circulating level of IGFBP-3 is inversely related to the risk of several common cancers, and that antiproliferative agents such as antiestrogens and retinoids act in part by up-regulating IGFBP-3 gene (IGFBP3) expression. Although approximately 50% of the substantial interindividual variability in circulating IGFBP-3 levels is known to have a genetic basis, the specific loci involved are unknown. Direct sequencing of genomic DNA specimens from a multiethnic population identified several single nucleotide polymorphisms in the promoter region of IGFBP3. For the most common single nucleotide polymorphism (nucleotide -202) found to be in Hardy-Weinberg equilibrium, genotype was highly correlated to circulating level of IGFBP-3 in 478 men from the Physicians' Health Study. In vitro, we documented significantly higher promoter activity of the A allele at the -202 locus compared with the C allele, consistent with the relationship observed between genotype and circulating IGFBP-3 (AA > AC > CC). A positive correlation was observed between circulating retinol levels and circulating IGFBP-3 levels; subset analysis by genotype showed that this relationship was only present among individuals carrying an A allele at -202 (AA > AC > CC). Tall individuals or individuals with a body mass index of 27 or greater had levels of circulating IGFBP-3 that were significantly higher when they possessed at least one A allele (AA > AC > CC). The IGFBP3 promoter region deserves investigation as a locus where polymorphic variation occurs frequently and may influence GH responsiveness, somatic growth, and possibly cancer risk.
胰岛素样生长因子（IGF）结合蛋白-3（IGFBP-3）是循环中IGF水平的主要决定因素，在临床上可用于评估生长激素缺乏症以及预测对生长激素治疗的反应。最近的研究表明，循环中IGFBP-3的水平与几种常见癌症的风险呈负相关，并且抗增殖剂如抗雌激素和视黄酸部分通过上调IGFBP-3基因（IGFBP3）的表达发挥作用。虽然已知循环中IGFBP-3水平个体间存在的显著差异约50%具有遗传基础，但具体涉及的基因座尚不清楚。对来自多民族人群的基因组DNA样本进行直接测序，在IGFBP3的启动子区域发现了几个单核苷酸多态性。对于发现处于哈迪-温伯格平衡的最常见单核苷酸多态性（核苷酸-202），在医师健康研究中的478名男性中，基因型与循环中IGFBP-3的水平高度相关。在体外，我们记录到-202位点的A等位基因启动子活性显著高于C等位基因，这与观察到的基因型与循环中IGFBP-3之间的关系一致（AA>AC>CC）。循环视黄醇水平与循环IGFBP-3水平之间存在正相关；按基因型进行的亚组分析表明，这种关系仅存在于-202位点携带A等位基因的个体中（AA>AC>CC）。身高较高或体重指数为27或更高的个体，当他们至少拥有一个A等位基因时（AA>AC>CC），其循环中IGFBP-3的水平显著更高。IGFBP3启动子区域值得作为一个经常发生多态性变异且可能影响生长激素反应性、体细胞生长以及可能影响癌症风险的基因座进行研究。
