Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators.
Novel promoter polymorphism in insulin-like growth factor-binding protein-3: correlation with serum levels and interaction with known regulators.
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DOI：
10.1210/jcem.86.3.7280
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发表时间：
2001-03
期刊：
影响因子：
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通讯作者：
C. Deal;Jing Ma;F. Wilkin;J. Paquette;F. Rozen;B. Ge;T. Hudson;M. Stampfer;M. Pollak
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文献类型：
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作者：
C. Deal;Jing Ma;F. Wilkin;J. Paquette;F. Rozen;B. Ge;T. Hudson;M. Stampfer;M. Pollak
胰岛素样生长因子（IGF）结合蛋白-3 （IGFBP-3）是血液中IGF水平的主要决定因素，在临床上对生长激素缺乏症的评估和对生长激素治疗反应的预测是有用的。最近的研究表明，IGFBP-3的循环水平与几种常见癌症的风险呈负相关，抗增殖药物如抗雌激素和类维生素a等部分通过上调IGFBP-3基因（IGFBP3）的表达而起作用。虽然已知循环IGFBP-3水平中大约50%的实质性个体间差异具有遗传基础，但涉及的具体位点尚不清楚。对来自多种族人群的基因组DNA标本进行直接测序，发现IGFBP3启动子区域存在几个单核苷酸多态性。对于Hardy-Weinberg平衡中发现的最常见的单核苷酸多态性（核苷酸-202），在医生健康研究的478名男性中，基因型与IGFBP-3循环水平高度相关。在体外实验中，我们发现-202位点上A等位基因的启动子活性明显高于C等位基因，这与基因型与循环IGFBP-3 （AA > AC > CC）之间的关系一致。循环视黄醇水平与循环IGFBP-3水平呈正相关；基因型亚群分析表明，这种关系仅存在于携带A等位基因-202 （AA > AC > CC）的个体中。高个子或体重指数大于等于27的人，当他们拥有至少一个a等位基因（AA > AC > CC）时，其循环IGFBP-3水平明显更高。IGFBP3启动子区域作为一个多态性变异频繁发生的位点值得研究，它可能影响生长激素的反应性、体细胞生长和可能的癌症风险。
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.