Identification of a regulatory SNP in the retinol binding protein 4 gene associated with type 2 diabetes in Mongolia
Identification of a regulatory SNP in the retinol binding protein 4 gene associated with type 2 diabetes in Mongolia
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DOI：
10.1007/s00439-006-0264-4
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发表时间：
2007-01-01
期刊：
影响因子：
5.3
通讯作者：
Iwamoto, Sadahiko
中科院分区：
文献类型：
--
作者：
Munkhtulga, Lkhagvasuren;Nakayama, Kazuhiro;Iwamoto, Sadahiko
血清中视黄醇结合蛋白4（RBP 4）水平的升高与胰岛素抵抗相关。为了进一步研究这一点，在蒙古人中对RBP 4的基因组区域进行了遗传调查，这些蒙古人作为一个群体正在遭受糖尿病的快速增加。采用DHPLC系统筛选RBP 4基因，对多个样本中出现异源双链峰的PCR片段进行直接测序，鉴定48例蒙古族糖尿病患者RBP 4基因的常见多态性。在511例对照组和281例2型糖尿病患者中进行单核苷酸多态性（SNPs）基因分型。通过报告基因分析和电泳迁移率变动分析对调控区SNPs的功能进行了评价。对功能性SNP与血清RBP 4水平或代谢参数之间的可能关联进行统计学评估。在RBP 4基因中鉴定出9个SNP。一项病例对照研究显示，即使在Bonferroni校正后，四种SNP的罕见等位基因也与糖尿病风险增加相关（-803，G > A，P = 0.0054;+5169，C > T，P = 0.0025;+6969，G > C，P = 0.0015;+7542，T > del，P = 0.0015）。-803 G > A SNP影响肝癌细胞系中的转录效率以及肝细胞核因子1 α与该基序的结合效率。此外，-803 A等位基因与糖尿病患者血清RBP 4水平升高相关。我们在蒙古族人群中发现了与2型糖尿病相关的RBP 4基因的功能性SNP。
Increased levels of retinol binding protein 4 (RBP4) in serum is associated with insulin resistance. To examine this further, the genomic region of RBP4 was genetically surveyed in Mongolian people, who as a group are suffering from a recent rapid increase in diabetes. The RBP4 gene was screened by DHPLC system, and the PCR fragments which showed heteroduplex peaks in multiple samples were followed by direct sequencing to identify common polymorphisms in 48 Mongolian diabetic samples. Identified single nucleotide polymorphisms (SNPs) were genotyped in 511 control and 281 type 2 diabetes samples. The functions of SNPs in the regulatory region were assessed by reporter gene assay and electrophoretic mobility shift assay. Possible association between functional SNPs and serum RBP4 levels or metabolic parameters was statistically assessed. Nine SNPs were identified in the RBP4 gene. A case-control study revealed that the rare alleles of four SNPs were associated with increased risk of diabetes, even after Bonferroni correction (-803, G > A, P = 0.0054; +5169, C > T, P = 0.0025; +6969, G > C, P = 0.0015; +7542, T > del, P = 0.0015). The -803 G > A SNP influenced the transcription efficiency in a hepatocarcinoma cell line as well as the binding efficiency of hepatocyte nuclear factor 1 alpha to the motif. In addition, the -803 A allele was associated with increased serum RBP4 levels in diabetic patients. We have identified a functional SNP in the RBP4 gene associated with type 2 diabetes in Mongolian people.