2型糖尿病易感基因TCF7L2的研究进展
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摘要
2型糖尿病(T2DM)的发生是多因素共同作用的结果,多基因变异是其中重要的因素,并且产生了T2DM的遗传易感性。全基因组关联性研究发现与T2DM密切相关的许多基因变异。核转录因子7类似物2(TCF7L2)基因是发现最早、研究较深入的基因之一,其表达产物转录因子TCF7L2介导Wnt信号通路,调节靶基因在全身各组织表达维持血糖平衡,该基因单核苷酸多态性变异通过影响Wnt信号通路调节胰岛素分泌及外周胰岛素抵抗,从而增加T2DM的易感性,其中rs7903146位点单核苷酸多态性变异与T2DM相关性密切,是目前研究的热点。
The occurrence of type 2 diabetes mellitus( T2 DM) results from a variety of factors. Multiple genetic variation is an important factor,which generates genetic susceptibility to T2 DM. From the genome-wide association study,many genetic variations closely associated with T2 DM have been found. Transcription factor 7 like 2( TCF7 L2) gene is one of the earliest genes to be found and deeply studied. Its expressed product is TCF7 L2 transcription factor mediating Wnt signaling pathway,maintaining blood sugar balance by regulating expression of target genes in various tissues. The single nucleotide polymorphisms variations affect insulin secretion and peripheral insulin resistance by influencing the Wnt signaling pathway conduction,therefore increase susceptibility to T2 DM. The single nucleotide polymorphisms at rs7903146 locus have greater relevance to T2 DM which is the research hotspot at present.
The occurrence of type 2 diabetes mellitus( T2 DM) results from a variety of factors. Multiple genetic variation is an important factor,which generates genetic susceptibility to T2 DM. From the genome-wide association study,many genetic variations closely associated with T2 DM have been found. Transcription factor 7 like 2( TCF7 L2) gene is one of the earliest genes to be found and deeply studied. Its expressed product is TCF7 L2 transcription factor mediating Wnt signaling pathway,maintaining blood sugar balance by regulating expression of target genes in various tissues. The single nucleotide polymorphisms variations affect insulin secretion and peripheral insulin resistance by influencing the Wnt signaling pathway conduction,therefore increase susceptibility to T2 DM. The single nucleotide polymorphisms at rs7903146 locus have greater relevance to T2 DM which is the research hotspot at present.
引文
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[2]Meigs JB,Shrader P,Sullivan LM,et al.Genotype score in addition to common risk factors for prediction of type 2 diabetes[J].N Engl J Med,2008,359(21):2208-2219.
[3]Kaminska D,Kuulasmaa T,Venesmaa S,et al.Adipose tissue TCF7L2 splicing is regulated by weight loss and associates with glucose and fatty acid metabolism[J].Diabetes,2012,61(11):2807-2813.
[4]Olsson LP,Welch C,Hansson O,et al.Tissue-specific alternative splicing of TCF7L2[J].Hum Mol Genet,2009,18(20):3795-3804.
[5]Chang YC,Chang TJ,Jiang YD,et al.Association study of the genetic polymorphisms of the transcription factor 7-like 2(TCF7L2)gene and type 2 diabetes in the Chinese population[J].Diabetes,2007,56:2631-2637.
[6]Badimon L,Borrell-Pages M.Wnt signaling in the vessel wall[J].Curr Opin Hematol,2017,24(3):230-239.
[7]Locke JM,Da Silva Xavier G,Rutter GA,et al.An alternative polyadenylation signal in TCF7L2 generates isoforms that inhibit T cell factor/lymphoid-enhancer factor(TCF/LEF)-dependent target genes[J].Diabetologia,2011,54(12):3078-3082.
[8]Mitchell RK,Mondragon A,Chen L,et al.Selective disruption of Tcf7l2 in the pancreaticβcell impairs secretory function and lowersβcell mass[J].Hum Mol Genet,2015,24(5):1390-1399.
[9]Shao W,Wang D,Chiang YT,et al.The wnt signaling pathway effector TCF7L2 controls gut and brain proglucagon gene expression and glucose homeostasis[J].Diabetes,2013,62(3):789-800.
[10]Zhou Y,Park SY,Su J,et al.TCF7L2 is a master regulator of insulin production and processing[J].Hum Mol Genet,2014,23(24):6419-6431.
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[12]Zhou Y,Zhang E,Berggreen C,et al.Survival of pancreatic beta cells is partly controlled by a TCF7L2-p53-p53INP1-dependent pathway[J].Hum Mol Genet,2012,21(1):196-207.
[13]夏佳佳,郑晓雅,刘婵,等.沉默TCF7L2对胰岛素抵抗Hep G2细胞胰岛素降解酶表达的调控作用观察[J].解放军医学杂志,2015,40(2):110-116.
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[15]Quyang D,Xu L,Zhang L,et al.MiR-181a-5p regulates 3T3-L1cell adipogenesis by targeting Smad7 and Tcf7l2[J].Acta Bioch Bioph Sin,2016,48(11):1034-1041.
[16]Karczewska-Kupczewska M,Stefanowicz M,Matulewicz N,et al.Wnt signaling genes in adipose tissue and skeletal muscle of humans with different degrees of insulin sensitivity[J].J Clin Endocr Metab,2016,101(8):3079-3087.
[17]Wilfred L,Weijuan S,Zhuolun S,et al.Liver-specific expression of dominant-negative transcription factor 7-like 2 causes progressive impairment in glucose homeostasis[J].Diabetes,2015,64(6):1923-1932.
[18]Grant SF,Thorleifsson G,Reynisdottir I,et al.Variant of transcription factor 7-like 2(TCF7L2)gene confers risk of type 2diabetes[J].Nat Genet,2006,38:320-323.
[19]Sale MM,Smith SG,Mychaleckyj JC,et al.Variants of the transcription factor 7-like 2(TCF7L2)gene are associated with type2 diabetes in an African-American population enriched for nephropathy[J].Diabetes,2007,56(10):2638-2642.
[20]Ruiz-Narváez EA.Redundant enhancers and causal variants in the TCF7L2 gene[J].Eur J Hum Genet,2014,22(11):1243-1246.
[21]张晓蕾,王玉霞,刘巍,等.沈阳地区人群TCF7L2基因rs7903146-T/C多态性与2型糖尿病的相关性[J].中国误诊学杂志,2012,12(2):255-256.
[22]赵珂,李新华,丁文宇.TCF7L2基因单核苷酸多态性与2型糖尿病关系的研究进展[J].山东医药,2016,56(14):99-101.
[23]Villareal DT,Robertson H,Bell GI,et al.TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by modulating incretin action[J].Diabetes,2010,59(2):479-485.
[24]Bailey KA,Savic D,Zielinski M,et al.Evidence of non-pancreatic beta cell-dependent roles of Tcf7l2 in the regulation of glucose metabolism in mice[J].Hum Mol Genet,2015,24(6):1646-1654.
[25]Lyssenko V,Lupi R,Marchetti P,et al.Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes[J].J Clin Invest,2007,117(8):2155-2163.
[26]Faerch K,Pilgaard K,Knop FK,et al.Incretin and pancreatic hormone secretion in Caucasian non-diabetic carriers of the TCF7L2 rs7903146 risk T allele[J].Diabetes Obes Metab,2013,15(1):91-95.
[27]Loos RJ,Franks PW,Francis RW,et al.TCF7L2 polymorphisms modulate proinsulin levels andβ-cell function in a British Europid population[J].Diabetes,2007,56:1943-1947.
[28]Asma S,Howard Eric W,Been Latonya F,et al.Abstract 570:A functional mutation in WNT16a up-regulates pancreatic expression of TCF7L2 variants through Wnt signaling pathway[J].Arterioscl Throm Vas,2013,33(5):A570.
[29]Xia Q,Chesi A,Manduchi E,et al.The type 2 diabetes presumed causal variant within TCF7L2 resides in an element that controls the expression of ACSL5[J].Diabetologia,2016,59(11):2360-2368.
[30]赵雪单,乔虹.TCF7L2基因多态性与2型糖尿病相关性[J].医学研究所学报,2010,23(3):305-307.
[31]Haupt A,Thamer C,Heni M,et al.Gene variants of TCF7L2influence weight loss and body composition during lifestyle intervention in a population at risk for type 2 diabetes[J].Diabetes,2010,59(3):747-750.
[32]Gallardo-Blanco HL,Villarreal-Perez JZ,Cerda-Flores RM,et al.Genetic variants in KCNJ11,TCF7L2 and HNF4A are associated with type 2 diabetes,BMI and dyslipidemia in families of Northeastern Mexico:A pilot study[J].Exp Ther Med,2017,13(2):523-529.
[33]Srivastava A,Mittal B,Prakash J,et al.A multianalytical approach to evaluate the association of 55 SNPs in 28 genes with obesity risk in North Indian adults[J].Am J Hum Biol,2016,29(2):1-17.
[34]Lyssenko V,Jonsson A,Almgren P,et al.Clinical risk factors,DNA variants,and the development of type 2 diabetes[J].N Engl J Med,2008,359(21):2220-2232.
[35]Redondo MJ,Geyer S,Steck AK,et al.TCF7L2 genetic variants contribute to phenotypic heterogeneity of type 1 diabetes[J].Diabetes Care,2018,41:311-317.
[36]Frch K,Vistisen D,Pacini G,et al.Insulin resistance is accompanied by increased fasting glucagon and delayed glucagon suppression in individuals with normal and impaired glucose regulation[J].Diabetes,2016,65(11):3473-3481.
[37]Smushkin G,Sathananthan M,Sathananthan A,et al.Diabetes-associated common genetic variation and its association with GLP-1concentrations and response to exogenous GLP-1[J].Diabetes,2012,61(5):1082-1089.
[2]Meigs JB,Shrader P,Sullivan LM,et al.Genotype score in addition to common risk factors for prediction of type 2 diabetes[J].N Engl J Med,2008,359(21):2208-2219.
[3]Kaminska D,Kuulasmaa T,Venesmaa S,et al.Adipose tissue TCF7L2 splicing is regulated by weight loss and associates with glucose and fatty acid metabolism[J].Diabetes,2012,61(11):2807-2813.
[4]Olsson LP,Welch C,Hansson O,et al.Tissue-specific alternative splicing of TCF7L2[J].Hum Mol Genet,2009,18(20):3795-3804.
[5]Chang YC,Chang TJ,Jiang YD,et al.Association study of the genetic polymorphisms of the transcription factor 7-like 2(TCF7L2)gene and type 2 diabetes in the Chinese population[J].Diabetes,2007,56:2631-2637.
[6]Badimon L,Borrell-Pages M.Wnt signaling in the vessel wall[J].Curr Opin Hematol,2017,24(3):230-239.
[7]Locke JM,Da Silva Xavier G,Rutter GA,et al.An alternative polyadenylation signal in TCF7L2 generates isoforms that inhibit T cell factor/lymphoid-enhancer factor(TCF/LEF)-dependent target genes[J].Diabetologia,2011,54(12):3078-3082.
[8]Mitchell RK,Mondragon A,Chen L,et al.Selective disruption of Tcf7l2 in the pancreaticβcell impairs secretory function and lowersβcell mass[J].Hum Mol Genet,2015,24(5):1390-1399.
[9]Shao W,Wang D,Chiang YT,et al.The wnt signaling pathway effector TCF7L2 controls gut and brain proglucagon gene expression and glucose homeostasis[J].Diabetes,2013,62(3):789-800.
[10]Zhou Y,Park SY,Su J,et al.TCF7L2 is a master regulator of insulin production and processing[J].Hum Mol Genet,2014,23(24):6419-6431.
[11]Shu L,Sauter NS,Schulthess FT,et al.Transcription factor 7 like2 regulates beta-cell survival and function in human pancreatic islets[J].Diabetes,2008,57(3):645-653.
[12]Zhou Y,Zhang E,Berggreen C,et al.Survival of pancreatic beta cells is partly controlled by a TCF7L2-p53-p53INP1-dependent pathway[J].Hum Mol Genet,2012,21(1):196-207.
[13]夏佳佳,郑晓雅,刘婵,等.沉默TCF7L2对胰岛素抵抗Hep G2细胞胰岛素降解酶表达的调控作用观察[J].解放军医学杂志,2015,40(2):110-116.
[14]Da Silva Xavier G,Mondragon A,Mourougavelou V,et al.Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice[J].Diabetologia,2017,60(6):1043-1050.
[15]Quyang D,Xu L,Zhang L,et al.MiR-181a-5p regulates 3T3-L1cell adipogenesis by targeting Smad7 and Tcf7l2[J].Acta Bioch Bioph Sin,2016,48(11):1034-1041.
[16]Karczewska-Kupczewska M,Stefanowicz M,Matulewicz N,et al.Wnt signaling genes in adipose tissue and skeletal muscle of humans with different degrees of insulin sensitivity[J].J Clin Endocr Metab,2016,101(8):3079-3087.
[17]Wilfred L,Weijuan S,Zhuolun S,et al.Liver-specific expression of dominant-negative transcription factor 7-like 2 causes progressive impairment in glucose homeostasis[J].Diabetes,2015,64(6):1923-1932.
[18]Grant SF,Thorleifsson G,Reynisdottir I,et al.Variant of transcription factor 7-like 2(TCF7L2)gene confers risk of type 2diabetes[J].Nat Genet,2006,38:320-323.
[19]Sale MM,Smith SG,Mychaleckyj JC,et al.Variants of the transcription factor 7-like 2(TCF7L2)gene are associated with type2 diabetes in an African-American population enriched for nephropathy[J].Diabetes,2007,56(10):2638-2642.
[20]Ruiz-Narváez EA.Redundant enhancers and causal variants in the TCF7L2 gene[J].Eur J Hum Genet,2014,22(11):1243-1246.
[21]张晓蕾,王玉霞,刘巍,等.沈阳地区人群TCF7L2基因rs7903146-T/C多态性与2型糖尿病的相关性[J].中国误诊学杂志,2012,12(2):255-256.
[22]赵珂,李新华,丁文宇.TCF7L2基因单核苷酸多态性与2型糖尿病关系的研究进展[J].山东医药,2016,56(14):99-101.
[23]Villareal DT,Robertson H,Bell GI,et al.TCF7L2 variant rs7903146 affects the risk of type 2 diabetes by modulating incretin action[J].Diabetes,2010,59(2):479-485.
[24]Bailey KA,Savic D,Zielinski M,et al.Evidence of non-pancreatic beta cell-dependent roles of Tcf7l2 in the regulation of glucose metabolism in mice[J].Hum Mol Genet,2015,24(6):1646-1654.
[25]Lyssenko V,Lupi R,Marchetti P,et al.Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes[J].J Clin Invest,2007,117(8):2155-2163.
[26]Faerch K,Pilgaard K,Knop FK,et al.Incretin and pancreatic hormone secretion in Caucasian non-diabetic carriers of the TCF7L2 rs7903146 risk T allele[J].Diabetes Obes Metab,2013,15(1):91-95.
[27]Loos RJ,Franks PW,Francis RW,et al.TCF7L2 polymorphisms modulate proinsulin levels andβ-cell function in a British Europid population[J].Diabetes,2007,56:1943-1947.
[28]Asma S,Howard Eric W,Been Latonya F,et al.Abstract 570:A functional mutation in WNT16a up-regulates pancreatic expression of TCF7L2 variants through Wnt signaling pathway[J].Arterioscl Throm Vas,2013,33(5):A570.
[29]Xia Q,Chesi A,Manduchi E,et al.The type 2 diabetes presumed causal variant within TCF7L2 resides in an element that controls the expression of ACSL5[J].Diabetologia,2016,59(11):2360-2368.
[30]赵雪单,乔虹.TCF7L2基因多态性与2型糖尿病相关性[J].医学研究所学报,2010,23(3):305-307.
[31]Haupt A,Thamer C,Heni M,et al.Gene variants of TCF7L2influence weight loss and body composition during lifestyle intervention in a population at risk for type 2 diabetes[J].Diabetes,2010,59(3):747-750.
[32]Gallardo-Blanco HL,Villarreal-Perez JZ,Cerda-Flores RM,et al.Genetic variants in KCNJ11,TCF7L2 and HNF4A are associated with type 2 diabetes,BMI and dyslipidemia in families of Northeastern Mexico:A pilot study[J].Exp Ther Med,2017,13(2):523-529.
[33]Srivastava A,Mittal B,Prakash J,et al.A multianalytical approach to evaluate the association of 55 SNPs in 28 genes with obesity risk in North Indian adults[J].Am J Hum Biol,2016,29(2):1-17.
[34]Lyssenko V,Jonsson A,Almgren P,et al.Clinical risk factors,DNA variants,and the development of type 2 diabetes[J].N Engl J Med,2008,359(21):2220-2232.
[35]Redondo MJ,Geyer S,Steck AK,et al.TCF7L2 genetic variants contribute to phenotypic heterogeneity of type 1 diabetes[J].Diabetes Care,2018,41:311-317.
[36]Frch K,Vistisen D,Pacini G,et al.Insulin resistance is accompanied by increased fasting glucagon and delayed glucagon suppression in individuals with normal and impaired glucose regulation[J].Diabetes,2016,65(11):3473-3481.
[37]Smushkin G,Sathananthan M,Sathananthan A,et al.Diabetes-associated common genetic variation and its association with GLP-1concentrations and response to exogenous GLP-1[J].Diabetes,2012,61(5):1082-1089.