Polymorphisms within the protein tyrosine phosphatase IB (PTPNI) gene promoter:: Functional characterization and association with type 2 diabetes and related metabolic traits
Polymorphisms within the protein tyrosine phosphatase IB (PTPNI) gene promoter:: Functional characterization and association with type 2 diabetes and related metabolic traits
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DOI：
10.1373/clinchem.2007.088146
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发表时间：
2007-09-01
影响因子：
9.3
通讯作者：
Adeli, Khosrow
中科院分区：
文献类型：
--
作者：
Meshkani, Reza;Taghikhani, Mohammad;Adeli, Khosrow
背景：蛋白酪氨酸磷酸酶113(PTPN1)使胰岛素受体去磷酸化，减弱胰岛素信号。PTPNI编码序列的多态与2型糖尿病(T2D)有不同程度的相关性。我们推测PTPNI基因启动子的变异可能与T2D及其相关代谢途径的发生有关。方法：采用聚合酶链式反应和变性高效液相色谱法对174例T2D患者和412名对照的PTPNI启动子进行了2.0kb的筛查。对糖尿病相关性状和单核苷酸多态基因进行关联分析。结果：共鉴定出1个常见的(-1023C>；A)和6个罕见的(-51delA、-451a>；G、-467T>；C、-1045G>；A、-1286-3bp-del和-1291-9bp-del)的PTPN1启动子。-1023(C)等位基因与T2D显著相关，在我们调整已确定的糖尿病危险因素后，T2D消失。在调整糖尿病危险因素后，非糖尿病组和糖尿病组中-1023C>；A和-51delA变异的等位基因对生化标记物均无显著影响。-51delA变异体使HepG2细胞荧光素酶基因表达降低2倍。EMSA显示-51delA与特定蛋白家族蛋白的结合弱于A等位基因。结论：PTPNI启动子变异-1023C>；A和-51delA(似乎具有功能)与本研究中的T2D或相关性状没有关联，但必须在更大的人群中进行研究，以揭示任何潜在的代谢关联。(C)2007年美国临床化学协会
Background: Protein tyrosine phosphatase 113 (PTPN1) dephosphorylates insulin receptors and attenuates insulin signaling. Polymorphisms in the coding sequence of PTPNI have been variably associated with type 2 diabetes (T2D). We hypothesized that variations within the PTPNI promoter might contribute to the development of T2D and related metabolic traits.Methods: We screened 2.0 kb of PTPNI promoter in 174 T2D patients and 412 controls using PCR and denaturing HPLC. Association analysis was performed between diabetes and related traits and single-nucleotide polymorphism genotypes. We functionally tested 2 variants (-1023C > A and -51delA) by measuring their influence on luciferase activity in HepG2 cells and performing the electrophoretic mobility shift assay (EMSA).Results: One common (-1023C>A) and 6 rare (-51delA, -451A > G, -467T > C, -1045G > A, -1286-3bp-del, and -1291-9bp-del) variants were identified the PTPN1 promoter. The -1023(C) allele had significant association with T2D that disappeared after we adjusted for established diabetes risk factors. The alleles of -1023C>A and -51delA variants did not show significant effects on the biochemical markers after adjustment for established diabetes risk factors in the nondiabetic and diabetic groups separately. The -51delA variant decreased luciferase gene expression in HepG2 cells by 2-fold. EMSA revealed a weaker binding of -51delA to specific protein family proteins compared with the A allele. The -1023C>A variant had no influence in either experiment.Conclusions: The PTPNI promoter variants -1023C>A and -51delA (which appears to be functional) were not associated with T2D or related traits in this study but must be investigated in a larger population to reveal any potential metabolic association. (c) 2007 American Association for Clinical Chemistry