PAX4、NeuroD1基因多态性与自身抗体阴性酮症倾向糖尿病的关联研究
|
摘要
酮症倾向糖尿病(ketosis-prone diabetes,KPD)是一种以无诱因的酮症或酮症酸中毒起病而临床表现异质性很大的综合症,它包括自身免疫性1型糖尿病(1A型)和胰岛自身抗体阴性的特发1型糖尿病(1B型)。目前对于胰岛自身抗体阴性的KPD的病因知之甚少,由于该类患者体内缺乏自身免疫破坏p细胞的证据,因此,遗传和环境因素可能是其主要病因,在遗传性因素中影响p细胞分化成熟和胰岛素分泌的转录因子如PAX4、NeuroD1、PDX1等近年来受到研究者的关注。但在已有的相关研究中缺乏中国人群的研究,有关多态性的关联分析手段也相对简单。因此本研究选择与p细胞分化成熟和胰岛素分泌有关的转录因子PAX4和NeuroD1基因作为候选基因,设计一个两步的病例-对照关联分析,即首先在小样本人群中应用变性高效液相色谱技术(DHPLC)进行PAX4基因突变筛查,从检测出的单核苷酸多态性(single nucleotide polymorphism, SNP)中选择等位基因频率>1%的4个SNP,加上我们在另一研究中已对NeuroD1基因筛查出的一个SNP,在所有样本中对两基因的5个SNP进行基因分型及关联分析。通过采用单点分析,单倍型分析与多点联合作用分析相结合的关联分析方法,探讨这些基因的多态性对中国汉族自身抗体阴性KPD易感性的影响。
第一部分胰岛自身抗体阴性酮症倾向糖尿病的PAX4基因突变筛查
目的：建立变性高效液相色谱技术(DHPLC)的检测方法,筛查中国汉族胰岛自身抗体阴性的酮症倾向糖尿病(KPD)的PAX4基因突变
设计：病例-对照研究
方法：采用变性高效液相色谱技术(DHPLC)结合直接测序法,检测141例胰岛自身抗体GAD-Ab和IA-2A阴性的酮症起病糖尿病患者和112例非糖尿病正常对照者的PAX4基因的九个外显子区的突变情况。
结果：
1.成功建立了DHPLC检测PAX4基因的方法。
2.DHPLC检测到PAX4基因的外显子1、4、5、9分别有2、137、41和86例出现异常峰型,经测序证实均有碱基改变,检出符合率100%。
3.共检测到PAX4基因9个外显子区的7种碱基改变,它们分别是：外显子1的错义突变Arg31Gln (G298A),外显子4的同义突变Gln173Gln (A725G, rs327517)和错义突变Lys147Arg (A649G),外显子5的错义突变Arg183Cys (C753T)、Arg192Ser (C780A, rs3824004)和Arg192His(G781A, rs2233580),外显子9的错义突变His321Pro (A1168C, rs712701)。其中外显子4的错义突变Lys147Arg (A649G)为新发现的突变位点。
结论：
在中国汉族人群中,PAX4基因有6种常见多态性改变,分别为Arg31Gln、Gln173Gln、Arg183Cys、Arg192Ser、Arg192His、His321Pro。
第二部分自身抗体阴性KPD的PAX4基因多态性关联研究
目的：探讨PAX4基因多态性与中国汉族胰岛自身抗体阴性酮症倾向糖尿病(KPD)的关系。
设计：病例-对照研究
方法：采用多聚酶链反应限制性片段长度多态性(PCR-RFLP)技术检测296例胰岛自身抗体GAD-Ab和IA-2A阴性的KPD患者、399例正常对照者的PAX4基因外显子9的多态性His321Pro的基因型。采用PCR-直接测序法检测PAX4基因外显子5的多态性Arg183Cys、Arg192Ser、Arg192His的基因型。分析PAX4基因各多态性与KPD的关系,同时分析各多态性位点所构成的单体型与KPD的关系。
结果：
1.自身抗体阴性的KPD患者PAX4 Arg183Cys的CT基因型和T等位基因频率与正常对照者比较,差异均无显著性。CT基因型患者与CC基因型患者的BMI(P=0.025)和FCP水平(P=0.024)比较差异均有显著性。
2.自身抗体阴性的KPD患者与正常对照组比较,Arg192Ser的AA基因型(0.7%vs0%,χ2=8.183,P=0.015)和A等位基因频率(6.6%VS 3.4%,OR=2.014,95%CI=1.218～3.329,P=0.005)明显增高。其中,男性(6.7%vs3.5%,P=0.03)和起病年龄<20岁(9.6% vs 3.4%,P=0.003)的KPD患者A等位基因频率高于正常对照。
3.自身抗体阴性的KPD患者PAX4基因Arg192His的AA基因型(16.9％vs10.1％,P=0.04)和A等位基因频率(10.6% VS6.8％,OR=1.641,95％CI=1.122～2.400,P=0.01)高于正常对照者。女性(10.8% vs 5.6%,P=0.04)和起病年龄≥20岁(11.1% vs 6.8%,P=0.007)的KPD患者的A等位基因频率高于正常对照。
4.自身抗体阴性的KPD患者PAX4基因His321Pro各基因型频率和等位基因频率与对照组比较,差异均无显著性(P>0.05)。男性KPD患者的CC基因型(15％vs 12.1％,χ2=6.74,P=0.03)和C等位基因频率(40.3％vs 31.9％,χ2=4.25,P=0.04)均高于女性KPD患者。
5、自身抗体阴性的KPD患者PAX4基因单体型AACC的频率(8.8％vs 5.2％,X2=7.199,OR=1.778,95％CI=1.164～2.717,P=0.007)和单体型CGAC的频率(4.0％vs2.0％,χ2=4.611,OR=2.065, 95％CI=1.087～3.923, P=0.032)均高于正常对照。而单体型CGCC在正常对照组中的频率高于起病年龄≥35岁KPD患者(35.7% vs28.7％,χ2=4.64,OR=0.725,95％CI=0.54～0.975,P=0.031).
结论：
1.PAX4基因Arg192Ser和Arg192His多态性与中国汉族胰岛自身抗体阴性的KPD有关联。
2.PAX4基因单体型AACC和单体型CGAC是中国汉族胰岛自身抗体阴性的KPD的易感单体型,单体型CGCC是起病年龄≥35岁KPD患者的保护性单体型。
第三部分NeuroD1基因A45T多态性与自身抗体阴性KPD的关系
目的：探讨NeuroD1基因A45T多态性与中国汉族胰岛自身抗体阴性酮症倾向糖尿病(KPD)的关系。
设计：病例-对照研究。
方法：采用PCR-测序法检测NeuroD1基因A45T基因型,分析NeuroD1基因A45T多态性与KPD的关系,同时分析NeuroD1基因A45T多态性与PAX4基因各多态性位点的交互作用对KPD的影响。
结果：
1.自身抗体阴性的KPD患者NeuroD1基因A45T的从基因型频率和A等位基因频率与NC组比较差异均无显著性(P=0.34)。对患者进行年龄和性别分层后仍没有发现NeuroD1基因A45T基因型频率与对照组有差别。
2.选择PAX4基因的3个多态位点C780A、G781A、C1168A与NeuroD1基因的Ala45Thr多态性位点进行对KPD的交互作用分析。结果显示,Ala45Thr多态性与PAX4的各多态性位点对KPD没有交互作用。
结论：
1. NeuroD1基因的Ala45Thr多态性与中国汉族自身抗体阴性的KPD没有相关性。
2. NeuroD1基因的Ala45Thr多态性位点与PAX4基因的C780A、-G781A、C1168A多态性位点在对KPD的易感性中没有基因-基因之间的交互作用。
Part 1 Screening and detection of Pax4 gene mutations in islet autoantibody-negative ketosis-prone diabetic patients
Objective:To establish a denaturing high performance liquid chromatography (dHPLC) method for detection mutations of paired box gene 4 (PAX4) in Chinese Han population with islet autoantibody-negative ketosis-prone diabetes (KPD).
Design:Case-control study
Methods:With dHPLC and direct sequencing, nine exons of PAX4 gene were screened for mutations in 141 patients with islet autoantibody-negative KPD, and 112 nondiabetic unrelated controls.
Results:
1. A dHPLC method for detection gene mutations of paired box gene 4 was established.
2. The dHPLC system detected 2、137、41 and 86 samples abnormal peak at exons 1、4、5、9 of PAX4 gene, and was confirmed by sequencing. The coincidence is 100%.
3. Seven single nucleotide variations were detected in nine exons of PAX4 gene. They are the missense mutation Arg31 Gln (G298A) in exon 1, synonymous mutation Gln173Gln (A725G, rs327517) and missense mutation Lys147Arg(A649g) in exon 4,missense mutations Arg183Cys (C753T)、Arg192Ser (C780A, rs3824004) and Arg192His (G781A, rs2233580)in exon 5; missense mutation His321Pro(A1168C, rs712701) in exon 9. Among these, the missense mutation Lys147Arg(A649g) in exon 4 was a new mutation.
Conclusion:
1. In Chinese Han population, six polymorphisms had been found, they are Arg31Gln、Gln173Gln、Arg183Cys、Arg192Ser、Arg192His and His321Pro.
Part2 Association of PAX4 gene polymorphism with islet autoantibody-negtive ketosis-prone diabetes
Objective:To investigate the association of PAX4 gene polymorphism with islet autoantibody-negative ketosis-prone diabetes(KPD) in Chinese Han population.
Design:case-control study.
Methods:A total of 296 patients with islet autoantibody-negative ketosis-prone diabetes and 399 nondiabetic unrelated controls were typed for the PAX4 gene excon 9 polymorphisms Pro321His by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method, and the PAX4 gene excon 5 polymorphisms were typed by PCR sequencing-based typing method. Association of PAX4 gene polymorphism with islet autoantibody-negative KPD and PAX4 gene haplotypes were analyzed in KPD group and NC group.
Result:
1. There was no significant difference in CT genotype frequency or T allele frequency between islet autoantibody-negative KPD subjects and normal controls. The BMI (P=0.025)and FCP(P=0.024) had significant difference in CT or CC patients.
2. Compared with normal controls, AA genotypic frequency(0.7% vs 0%,μ2=8.183, P=0.015) and A allele freuency (6.6% vs 3.4%, OR= 2.014, 95%CI=1.218～3.329,P=0.005) of Arg192Ser were higher in islet autoantibody-negtive KPD subjects. The A allele frequency in male(6.7% vs 3.5%,P=0.03) or onset age<20yr (9.6% vs 3.4%,P=0.003)in KPD subjects were significant higher than in normal controls.
3. AA genotypic frequency(16.9% vs 10%,P=0.04) and A allele frequency (10.6% vs 6.8%, OR=1.641,95%CI=1.122～2.400, P=0.01) of PAX4 Arg192His were significant different between islet autoantibody-negtive KPDs and normal controls. The A allele frequency in female (10.8% vs 5.6%, P=0.04) or onset age≥20 yr (11.1% vs 6.8%, P=0.007) in KPD subjects were significant higher than that in normal controls.
4. There were no significant difference(p>0.05)of PAX4 His321Pro between islet autoantibody-negative KPDs and normal controls. CC genotype frequency(15% vs 12.1%,χ2=6.74, P=0.03) and C allele frequency (40.3% vs 31.9%,χ2=4.25,P=0.04) in male were significant higher than that in females.
5. Haplotype AACC frequency (8.8%vs5.2%,χ2=7.199, OR=1.778, 95%CI=1.164～2.717,P=0.007) and haplotype CGAC freuency (4.0%vs2.0%,χ2=4.611, OR=2.065,95%CI=1.087～3.923,P=0.032) of PAX4 were significant higher in islet autoantibody-negtive KPD patients than those in normal controls, while the haplotype CGCC frequency in KPD patients at onset age≥35yr is significantly lower than that in normal controls (35.7% vs 28.7%,χ2=4.64, P=0.031, OR=0.725,95%CI=0.54～0.975)
Conclusions:
1. In Chinese Han population, PAX4 gene polymorphism Arg192Ser and Arg192His may be associated with islet autoantibody negative KPD.
2. In Chinese Han population, haplotypes AACC and CGAC may be susceptive haplotypes for islet autoantibody-negative KPD, and haplotypes CGCC was a protective haplotype for islet autoantibody-negtive KPD at onset age≥35yr.
Part 3 Relationship of NeuroDl polymorphism A45T with islet autoantibody-negative kerosis-prone diabetes
Objective:To study the relationship between the polymorphism A45T of NeuroDl and islet autoantibody-negative KPD in Chinese Han population, and investigate the interactive effects of NeuroD1 A45T and PAX4 gene polymorphism C780A、G781A and C1168A on islet autoantibody-negtive KPD.
Design:Case-control study.
Methods:A total of 296 patients with islet autoantibody-negative ketosis-prone diabetes and 399 nondiabetic unrelated controls were typed for the NeuroD A45T polymorphisms by PCR sequencing-based typing method. The distribution and characteristics of NeuroDl genotypes were studied in KPD group and NC group. The interaction of NeuroDl A45T and PAX4 C780A,G781A,C1168A in islet autoantibody-negative KPD were also investigated.
Results:
1. There was no significant difference in frequency of AA genotypes and A allele of NeruoDl polymorphism A45T between autoantibody-negative KPD patients and control subjects (p=0.34). No significant difference was been found in genotypic frequency of NeuroDl A45T in KPD patients and control subjects when patients were stratified according to age or sex.
2. Three polymorphisms of PAX4 gene, C780A, G781A and C1168A, had been selected to analyze the correlation with NeuroD1 Ala45Thr. The result showed there was no interaction of Ala45Thr and the PAX4 polymorphisms.
Conclusion:
1. There was no associated NeuroDl polymorphism Ala45Thr with islet auto-antibodies negative KPD in Chinese Han population.
2. There was no gene-gene interaction of NeuroD1 polymorphism Ala45Thr and the PAX4 polymorphisms C780A, G781A and C1168A in susceptive of KPD.
第一部分胰岛自身抗体阴性酮症倾向糖尿病的PAX4基因突变筛查
目的：建立变性高效液相色谱技术(DHPLC)的检测方法,筛查中国汉族胰岛自身抗体阴性的酮症倾向糖尿病(KPD)的PAX4基因突变
设计：病例-对照研究
方法：采用变性高效液相色谱技术(DHPLC)结合直接测序法,检测141例胰岛自身抗体GAD-Ab和IA-2A阴性的酮症起病糖尿病患者和112例非糖尿病正常对照者的PAX4基因的九个外显子区的突变情况。
结果：
1.成功建立了DHPLC检测PAX4基因的方法。
2.DHPLC检测到PAX4基因的外显子1、4、5、9分别有2、137、41和86例出现异常峰型,经测序证实均有碱基改变,检出符合率100%。
3.共检测到PAX4基因9个外显子区的7种碱基改变,它们分别是：外显子1的错义突变Arg31Gln (G298A),外显子4的同义突变Gln173Gln (A725G, rs327517)和错义突变Lys147Arg (A649G),外显子5的错义突变Arg183Cys (C753T)、Arg192Ser (C780A, rs3824004)和Arg192His(G781A, rs2233580),外显子9的错义突变His321Pro (A1168C, rs712701)。其中外显子4的错义突变Lys147Arg (A649G)为新发现的突变位点。
结论：
在中国汉族人群中,PAX4基因有6种常见多态性改变,分别为Arg31Gln、Gln173Gln、Arg183Cys、Arg192Ser、Arg192His、His321Pro。
第二部分自身抗体阴性KPD的PAX4基因多态性关联研究
目的：探讨PAX4基因多态性与中国汉族胰岛自身抗体阴性酮症倾向糖尿病(KPD)的关系。
设计：病例-对照研究
方法：采用多聚酶链反应限制性片段长度多态性(PCR-RFLP)技术检测296例胰岛自身抗体GAD-Ab和IA-2A阴性的KPD患者、399例正常对照者的PAX4基因外显子9的多态性His321Pro的基因型。采用PCR-直接测序法检测PAX4基因外显子5的多态性Arg183Cys、Arg192Ser、Arg192His的基因型。分析PAX4基因各多态性与KPD的关系,同时分析各多态性位点所构成的单体型与KPD的关系。
结果：
1.自身抗体阴性的KPD患者PAX4 Arg183Cys的CT基因型和T等位基因频率与正常对照者比较,差异均无显著性。CT基因型患者与CC基因型患者的BMI(P=0.025)和FCP水平(P=0.024)比较差异均有显著性。
2.自身抗体阴性的KPD患者与正常对照组比较,Arg192Ser的AA基因型(0.7%vs0%,χ2=8.183,P=0.015)和A等位基因频率(6.6%VS 3.4%,OR=2.014,95%CI=1.218～3.329,P=0.005)明显增高。其中,男性(6.7%vs3.5%,P=0.03)和起病年龄<20岁(9.6% vs 3.4%,P=0.003)的KPD患者A等位基因频率高于正常对照。
3.自身抗体阴性的KPD患者PAX4基因Arg192His的AA基因型(16.9％vs10.1％,P=0.04)和A等位基因频率(10.6% VS6.8％,OR=1.641,95％CI=1.122～2.400,P=0.01)高于正常对照者。女性(10.8% vs 5.6%,P=0.04)和起病年龄≥20岁(11.1% vs 6.8%,P=0.007)的KPD患者的A等位基因频率高于正常对照。
4.自身抗体阴性的KPD患者PAX4基因His321Pro各基因型频率和等位基因频率与对照组比较,差异均无显著性(P>0.05)。男性KPD患者的CC基因型(15％vs 12.1％,χ2=6.74,P=0.03)和C等位基因频率(40.3％vs 31.9％,χ2=4.25,P=0.04)均高于女性KPD患者。
5、自身抗体阴性的KPD患者PAX4基因单体型AACC的频率(8.8％vs 5.2％,X2=7.199,OR=1.778,95％CI=1.164～2.717,P=0.007)和单体型CGAC的频率(4.0％vs2.0％,χ2=4.611,OR=2.065, 95％CI=1.087～3.923, P=0.032)均高于正常对照。而单体型CGCC在正常对照组中的频率高于起病年龄≥35岁KPD患者(35.7% vs28.7％,χ2=4.64,OR=0.725,95％CI=0.54～0.975,P=0.031).
结论：
1.PAX4基因Arg192Ser和Arg192His多态性与中国汉族胰岛自身抗体阴性的KPD有关联。
2.PAX4基因单体型AACC和单体型CGAC是中国汉族胰岛自身抗体阴性的KPD的易感单体型,单体型CGCC是起病年龄≥35岁KPD患者的保护性单体型。
第三部分NeuroD1基因A45T多态性与自身抗体阴性KPD的关系
目的：探讨NeuroD1基因A45T多态性与中国汉族胰岛自身抗体阴性酮症倾向糖尿病(KPD)的关系。
设计：病例-对照研究。
方法：采用PCR-测序法检测NeuroD1基因A45T基因型,分析NeuroD1基因A45T多态性与KPD的关系,同时分析NeuroD1基因A45T多态性与PAX4基因各多态性位点的交互作用对KPD的影响。
结果：
1.自身抗体阴性的KPD患者NeuroD1基因A45T的从基因型频率和A等位基因频率与NC组比较差异均无显著性(P=0.34)。对患者进行年龄和性别分层后仍没有发现NeuroD1基因A45T基因型频率与对照组有差别。
2.选择PAX4基因的3个多态位点C780A、G781A、C1168A与NeuroD1基因的Ala45Thr多态性位点进行对KPD的交互作用分析。结果显示,Ala45Thr多态性与PAX4的各多态性位点对KPD没有交互作用。
结论：
1. NeuroD1基因的Ala45Thr多态性与中国汉族自身抗体阴性的KPD没有相关性。
2. NeuroD1基因的Ala45Thr多态性位点与PAX4基因的C780A、-G781A、C1168A多态性位点在对KPD的易感性中没有基因-基因之间的交互作用。
Part 1 Screening and detection of Pax4 gene mutations in islet autoantibody-negative ketosis-prone diabetic patients
Objective:To establish a denaturing high performance liquid chromatography (dHPLC) method for detection mutations of paired box gene 4 (PAX4) in Chinese Han population with islet autoantibody-negative ketosis-prone diabetes (KPD).
Design:Case-control study
Methods:With dHPLC and direct sequencing, nine exons of PAX4 gene were screened for mutations in 141 patients with islet autoantibody-negative KPD, and 112 nondiabetic unrelated controls.
Results:
1. A dHPLC method for detection gene mutations of paired box gene 4 was established.
2. The dHPLC system detected 2、137、41 and 86 samples abnormal peak at exons 1、4、5、9 of PAX4 gene, and was confirmed by sequencing. The coincidence is 100%.
3. Seven single nucleotide variations were detected in nine exons of PAX4 gene. They are the missense mutation Arg31 Gln (G298A) in exon 1, synonymous mutation Gln173Gln (A725G, rs327517) and missense mutation Lys147Arg(A649g) in exon 4,missense mutations Arg183Cys (C753T)、Arg192Ser (C780A, rs3824004) and Arg192His (G781A, rs2233580)in exon 5; missense mutation His321Pro(A1168C, rs712701) in exon 9. Among these, the missense mutation Lys147Arg(A649g) in exon 4 was a new mutation.
Conclusion:
1. In Chinese Han population, six polymorphisms had been found, they are Arg31Gln、Gln173Gln、Arg183Cys、Arg192Ser、Arg192His and His321Pro.
Part2 Association of PAX4 gene polymorphism with islet autoantibody-negtive ketosis-prone diabetes
Objective:To investigate the association of PAX4 gene polymorphism with islet autoantibody-negative ketosis-prone diabetes(KPD) in Chinese Han population.
Design:case-control study.
Methods:A total of 296 patients with islet autoantibody-negative ketosis-prone diabetes and 399 nondiabetic unrelated controls were typed for the PAX4 gene excon 9 polymorphisms Pro321His by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method, and the PAX4 gene excon 5 polymorphisms were typed by PCR sequencing-based typing method. Association of PAX4 gene polymorphism with islet autoantibody-negative KPD and PAX4 gene haplotypes were analyzed in KPD group and NC group.
Result:
1. There was no significant difference in CT genotype frequency or T allele frequency between islet autoantibody-negative KPD subjects and normal controls. The BMI (P=0.025)and FCP(P=0.024) had significant difference in CT or CC patients.
2. Compared with normal controls, AA genotypic frequency(0.7% vs 0%,μ2=8.183, P=0.015) and A allele freuency (6.6% vs 3.4%, OR= 2.014, 95%CI=1.218～3.329,P=0.005) of Arg192Ser were higher in islet autoantibody-negtive KPD subjects. The A allele frequency in male(6.7% vs 3.5%,P=0.03) or onset age<20yr (9.6% vs 3.4%,P=0.003)in KPD subjects were significant higher than in normal controls.
3. AA genotypic frequency(16.9% vs 10%,P=0.04) and A allele frequency (10.6% vs 6.8%, OR=1.641,95%CI=1.122～2.400, P=0.01) of PAX4 Arg192His were significant different between islet autoantibody-negtive KPDs and normal controls. The A allele frequency in female (10.8% vs 5.6%, P=0.04) or onset age≥20 yr (11.1% vs 6.8%, P=0.007) in KPD subjects were significant higher than that in normal controls.
4. There were no significant difference(p>0.05)of PAX4 His321Pro between islet autoantibody-negative KPDs and normal controls. CC genotype frequency(15% vs 12.1%,χ2=6.74, P=0.03) and C allele frequency (40.3% vs 31.9%,χ2=4.25,P=0.04) in male were significant higher than that in females.
5. Haplotype AACC frequency (8.8%vs5.2%,χ2=7.199, OR=1.778, 95%CI=1.164～2.717,P=0.007) and haplotype CGAC freuency (4.0%vs2.0%,χ2=4.611, OR=2.065,95%CI=1.087～3.923,P=0.032) of PAX4 were significant higher in islet autoantibody-negtive KPD patients than those in normal controls, while the haplotype CGCC frequency in KPD patients at onset age≥35yr is significantly lower than that in normal controls (35.7% vs 28.7%,χ2=4.64, P=0.031, OR=0.725,95%CI=0.54～0.975)
Conclusions:
1. In Chinese Han population, PAX4 gene polymorphism Arg192Ser and Arg192His may be associated with islet autoantibody negative KPD.
2. In Chinese Han population, haplotypes AACC and CGAC may be susceptive haplotypes for islet autoantibody-negative KPD, and haplotypes CGCC was a protective haplotype for islet autoantibody-negtive KPD at onset age≥35yr.
Part 3 Relationship of NeuroDl polymorphism A45T with islet autoantibody-negative kerosis-prone diabetes
Objective:To study the relationship between the polymorphism A45T of NeuroDl and islet autoantibody-negative KPD in Chinese Han population, and investigate the interactive effects of NeuroD1 A45T and PAX4 gene polymorphism C780A、G781A and C1168A on islet autoantibody-negtive KPD.
Design:Case-control study.
Methods:A total of 296 patients with islet autoantibody-negative ketosis-prone diabetes and 399 nondiabetic unrelated controls were typed for the NeuroD A45T polymorphisms by PCR sequencing-based typing method. The distribution and characteristics of NeuroDl genotypes were studied in KPD group and NC group. The interaction of NeuroDl A45T and PAX4 C780A,G781A,C1168A in islet autoantibody-negative KPD were also investigated.
Results:
1. There was no significant difference in frequency of AA genotypes and A allele of NeruoDl polymorphism A45T between autoantibody-negative KPD patients and control subjects (p=0.34). No significant difference was been found in genotypic frequency of NeuroDl A45T in KPD patients and control subjects when patients were stratified according to age or sex.
2. Three polymorphisms of PAX4 gene, C780A, G781A and C1168A, had been selected to analyze the correlation with NeuroD1 Ala45Thr. The result showed there was no interaction of Ala45Thr and the PAX4 polymorphisms.
Conclusion:
1. There was no associated NeuroDl polymorphism Ala45Thr with islet auto-antibodies negative KPD in Chinese Han population.
2. There was no gene-gene interaction of NeuroD1 polymorphism Ala45Thr and the PAX4 polymorphisms C780A, G781A and C1168A in susceptive of KPD.
引文
[1]Sohngwi E,Gautier JF. Adult-onset idiopathic Type 1 or ketosis-prone type2 diabetes:evidence to revisit diabetes classification. Diabetologia,2002,45: 283-285.
[2]Mauvais-Jarvis F, Sobngwi E, Porcher R; et al. Ketosis-prone type 2 diabetes in patients of sub-Saharan African origin:clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance.Diabetes.2004;53(3): 645-653.
[3]Kitabchi AE. Ketosis-prone diabetes-a new subgroup of patients with atypical type 1 and type 2 diabetes? J Clin Endocrinol Metab.2003;88(11):5087-5089.
[4]Maldonado MM, Hampe CS, Gaur LK,et al. Ketosis-prone diabetes:dissection of a heterogeneous syndrome using an immunogenetic and β-cell functional classification, prospective analysis,and clinical outcomes. J Clin Endocrinol Metab,2003,88:5090-5098.
[5]周智广,张弛,张冬梅等.特发1型糖尿病的临床特征及其亚型诊断探讨.中华糖尿病杂志,2004,12(2)：79-85
[6]张驰.酮症倾向糖尿病的异质性及分型诊断研究.[博士学位论文].长沙,中南大学,2005.
[7]张冬梅,周智广,胡白瑛,等.自发酮症起病的肥胖糖尿病患者临床特征和分型探讨.中华内分泌代谢杂志,2003,19(3)：221-224
[8]Mauvais-Jarvis F,Smith SB,May CL,et al.PAX4 gene variations predispose to ketosis-prone diabetes. Human Molec Genet,2004,13:3151-3159.
[9]Sohngwi E,Gautier JF,Riveline JP,et al. Ketosis-prone diabetes is associated to glucose-6-phosphate dehydrogenase deficiency in Afro-Caribbean patients (Abstract). Diabetes,2003,52(suppl.1):A356.
[10]Sohngwi E,Gautier JF,Kevorkian JP,et al. High prevalence of glucose-6-phosphate dehydrogenase deficiency without gene mutation suggests a novel genetic mechanism predisposing to ketosis-prone diabetes. Clin Endocrinol Metab.2005,90(8):4446-51
[11]Sobngwi E,Choukem SP,Agbalika F,et al. Ketosis-prone type2 diabetes mellitus and human Herpesvirus 8 infection in Sub-Saharan Africans. JAMA,2008, 299(23):2770-2776.
[12]D.Zhang, Z.Zhou, L. Li,et al.Islet autoimmunity and genetic mutations in Chinese subjects initially thought to have Type 1B diabetes. Diabetic Medicine, 2005,23,67-71
[13]Banerji MA,Chaiken RL,Huey H,et al. GAD antibody negative NIDDM in adult black subjects with diabetic ketoacidosis and increased frequency of human leukocyte antigen DR3 and DR4.Flatbush diabetes. Diabetes,1994,43:741-745.
[14]Davis TM,Zimmet P,Davis WA,et al. Autoantibodies to glutamic acid decardoxylase in diabetic patients from a multi-ethnic Austrlian community:the Fremantle Diabetes Study. Diabet Med,2000,17:667-674.
[15]Todd AL,Ng WY,Lui KF,et al. Low prevalence of autoimmune diabetes markers in a mixed ethnic population of Singaporean diabetics. Intern Med J,2004,34:24-30
[16]Sosa-Pineda B, Chowdhury K, Torres M,et al. The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas. Nature, 1997,386:399-402.
[17]Yoshinori S, Tokio S, Hiroto F,et al. A Missense Mutation of Pax4 Gene (R121W) Is Associated With Type 2 Diabetes in Japanese. Diabetes, 2001,50:2864-2869,
[18]Dupont S, Vionnet N, Chevre JC,et al. No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in Type Ⅱ diabetes in France. Diabetologia,1999,42(4):480-4.
[19]Winter WE,Nakamura M,House DV. Monogenic diabetes mellitus in youth. The MODY syndromes. Endocrinol Metab Clin North AM,1999,28(4):765-85.
[20]Dumonteil E, Philippe J. Insulin gene:organization,expression and regulation. Diabete Metab,1996,22:164-173.
[21]Kim JW, Seghers V,Cho JH,et al. Transactivation of the miuse sulfonylurea receptor 1 gene by BETA2/NeuroD. Mol Endocrinol,2002,16:1097-1107.
[22]Naya FJ, Huang HP, Qiu Y,et al. Diabete,defective pancreatic morphogenesis,and abnormal enteroendocrine differentiation in BETA2/NeuroD-deficient mice. Genes.Dev,1997,11(18):2323-2334.
[23]Huang HP, Chu K,Nemoz-Gaillard E,et al, Neogenesis of beta-cells in adult BETA2/NeuroD-deficient mice. Mol Endocrinol,2002,16(3):541-551.
[24]Hansen L. Candidate gene and late-onset type 2 diabetes mellitus:Susceptibility genes or common polymorphism? Dan Med Bull,2003,50:320-346.
[25]Malecki MT, Klupa T, Moczulski DK,et al. The Ala45Thr polymorphism of BETA2/NeuroD1 gene and susceptibility to type 1 diabetes mellitus in caucasians. Exp Clin Endocrinol Diabetes.2003;111(5):251-4.
[26]Iwata I, Nagafuchi S, Nakashima H,et al. Association of polymorphism in the NeuroD1/Beta2 gene with Type 1 diabetes in the Japanese. Diabetes,1999, 48(2):416-419
[27]Yamada S, Motohashi Y, Yanagawa T,et al. NeuroD1/Beta2 gene C→A polymorphism may affect onset pattern of type1 diabetes in Japanese. Diabetes Care,2001,24:1438-1441.
[28]Dupont S, Dina C, Hani EH, et al. Absence of replication in the French population of the association between beta 2/NEUROD-A45T polymorphism and type 1 diabetes. Diabetes Metab 1999,25:516-517.
[29]Awata T, Inoue K, Inoue I, et al. Lack of association of the Ala45Thr variant in the NeuroD/BETA2 with type 1 diabetes in Japanese. Diab Res Clin Pract.2000,49:61-63
[30]徐焱成,叶林秀,朱宜莲,等.神经源分化因子基因多态性与2型糖尿病的关联性研究.中华医学遗传学杂志,2002,19(6)：484-487
[31]Limei Liu, Weiping Jia, Taishan Zheng,et al.Ala45Thr variation in neuroDl gene is associated with early-onset type 2 diabetes with or without diabetic pedigree in Chinese. Mol Cell.Bioche.2006,290:199-204.
[32]叶林秀,徐焱成,朱宜莲,等.1型糖尿病病人神经源分化因子NeuroD/BETA2基因多态性研究.中国糖尿病杂志,2003,11(3)：216-217
[1]Umpierrez GE, Woo W, Hagopian WA, Isaacs SD, Palmer JP, Gaur LK, et al. Immunogenetic analysis suggests different pathogenesis for obese and lean African-Americans with diabetic ketoacidosis. Diabetes Care.1999;22:1517-23.
[2]Mauvais-Jarvis F, Sobngwi E, Porcher R, et al. Ketosis-prone type 2 diabetes in patients of sub-Saharan African origin:clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance. Diabetes.2004;53: 645-53.
[3]Ashok Balasubramanyam, Gilberto Garza, Lucille Rodriguez,et al. Accuracy and Predictive Value of Classification Schemes for Ketosis-Prone Diabetes. Diabetes Care,2006,29:2575-2579
[4]Maldonado MM,Hampe CS,Gaur LK,et al.Ketosis-prone diabetes:dissection of a heterogeneous syndrome using an immunogenetic and β-cell functional classification, prospective analysis, and clinical outcomes. J Clin Endocrinol Metab,2003,88:5090-5098.
[5]Imagawa A,Hanafusa T,Uchigata Y,et al. Different contribution of class Ⅱ HLA in fulminant and typical autoimmune type 1 diabetes mellitus. Diabetologia, 2005,48:294-300
[6]周智广,张驰,张冬梅等.特发1型糖尿病的临床特征及其亚型诊断探讨.中华内糖尿病杂志,2004,12(2)：79-85
[7]Sosa-Pineda B, Chowdhury K, Torres M,et al. The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas. Nature, 1997,386:399-402.
[8]Biason-Lauber A, Boehm B, Lang-Muritano M, et al. Association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity. Diabetologia,2005,48:900-905
[9]Hermann R, Mantere J, Lipponen K,et al. Lack of Association of PAX4 Gene With Type 1 Diabetes in the Finnish and Hungarian Populations. Diabetes 2005,54:2816-2819
[10]Yoshinori S,Tokio S,Hiroto F,et al. A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese. Diabetes,2001,50:2864-2869.
[11]Yoshiharu Tokuyama, Kana Matsui, Toshiharu Ishizuka,et al. The Arg121Trp variant in PAX4 gene is associated with beta-cell dysfunction in Japanese subjects with type 2 diabetes mellitus. Metabolism,2006,55(2):213-216
[12]Mauvais-Jarvis F,Smith SB,May CL,et al.PAX4 gene variations predispose to ketosis-prone diabetes. Human Molecular Genetics,2004,13:3151-3159.
[13]Nattachet Plengvidhya, Suwattanee Kooptiwut, Napat Songtawee,et al. PAX4 Mutations in Thais with Maturity Onset Diabetes of the Young. The Journal of Clinical Endocrinology & Metabolism.2007,92(7):2821-2826
[14]张云,肖新华,王姮等.PAX4基因A1168C多态性与中国汉族人1型糖尿病的相关性.中国医学科学院学报,2007,29(3)：370-373
[15]Xiao W., Oefner. P.J. Denaturing high-performance liquid chromatography:A review. Hum Mutat,2001,17(6):439-74
[16]Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care,2001,24:131-15
[17]黄干,周智广,彭健,等.35S标记重组人GAD65抗原检测糖尿病患者GAD-Ab指数.中华核医学杂志,2003,23：82-86.
[18]萨姆布鲁克J,弗里奇EF,曼尼阿蒂斯T.分子克隆实验指南(金冬雁译).第二版．北京：科学出版社,1992.
[19]Taliani MR,Roberts SC,Dukek BA,et al. Sensitivity and specificity of denaturing high-pressure liquid chromatography for unknown protein C gene mutations. Genet Test.2001,Spring;5(1):39-44.
[20]Oefner PJ,Underhill PA. Comparative DNA sequencing by denaturing high-performance liquid chromatography(DHPLC). Am J Hum Genet,1995, 57:A266.
[21]Spiegelman JI,Mindrins MN,Oefner PJ. High accuracy DNA sequence variation screening by DHPLC. BioTechniques 2000,29(5):1084-1092.
[22]O'Donovan M C,Oefner P J,Roberts S,et al. Blind analysis of denaturing high performance liquid chromatography as a tool for mutation detection. Genomics, 1998,52(1):44-49.
[23]Jones A C, Austin J,Hansen N,et al. Optimal temperature selection for mutation detection by denaturing HPLC and comparison to single-stranded conformation polymorphism and fieteroduplex analysis.Clin. Chem.1999,45(8 Pt 1): 1133-1140.
[24]Gross E,Arnold N,Pfeifer K,et al. Identification of specific BRCA1 and BRCA2 variants by DHPLC. Hum. Mutat.2000,16(4):345-353.
[25]Jiang WY,Chen LM,Lin QD,et al. Denaturing high-performance liquid chromatography technique platform applied to screen G6PD deficient variants. Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2005,22(6):607-611.
[26]Rachel Howarth Catharina Yearwood John F. Harvey. Application of dHPLC for Mutation Detection of the Fibrillin-1 Gene for the Diagnosis of Marfan Syndrome in a National Health Service Laboratory. Genetic Testing,2007,11(2):146-152
[27]吴柏林,朱建中.变性高效液相色谱基因扫描技术在人类疾病基因诊断中的应用.中华医学遗传学杂志,2004,21(5)：
[28]韩伟,楼定华,王竞,等.变性高效液相色谱分析法在人类基因组单核苷酸多态性检测中的应用.浙江大学学报(医学版),2005,34(3)：248-254
[1]Balasubramanyam AGG, Rodriguez L, Hampe C, et al:Accuracy and predictive value of classification schemes for ketosis-prone diabetes mellitus (KPDM). Diabetes Care,2006,29:2575-2579
[2]Imagawa A,Hanafusa T,Uchigata Y,et al. Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus. Diabetologia,2005,48:294-300
[3]周智广,张驰,张冬梅等.特发1型糖尿病的临床特征及其亚型诊断探讨.中华内糖尿病杂志,2004,12(2)：79-85
[4]Mauvais-Jarvis F,Sobngwi E,Porcher R,et al.Ketosis-prone type 2 diabetes in patients of Sub-Saharan African origin:clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance. Diabetes,2004,53:645-653.
[5]Mauvais-Jarvis F,Smith SB,May CL,et al.PAX4 gene variations predispose to ketosis-prone diabetes. [J]. Human Molecular Genetics,2004,13: 3151-3159.
[6]Sosa-Pineda, B., K. Chowdhury, M. Torres, et al. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature.1997,386:399-402.
[7]Holm P, Rydlander B, Luthman H, et al. Interaction and association analysis of a type 1 diabetes susceptibility locus on chromosome 5q11-q13 and the 7q32 chromosomal region in Scandinavian families. Diabetes, 2004,53:1584-1591
[8]Thierry Brun, Isobel Franklin, Luc St-Onge,et al. The diabetes-linked transcription factor PAX4 promotes β-cell proliferation and survival in rat and human islets. JCB,2004,167(6):1123-1135
[9]Mauvais-Jarvis F,Smith SB,Le May C,et al. PAX4 gene variations predispose to ketosis-prone diabetes. Hum Mol Genet,2004,13 (24): 3151-3159.
[10]Shimajiri Y, Sanke T, Furuta H, et al. A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese.. Diabetes,2001,50: 2864-2869.
[11]王建明,周智广,文建新,等.谷氨酸脱羧酶(GAD65)自身抗体的放射配体法.中国糖尿病杂志,1997,5(2)：85-88.
[12]黄干,周智广,王建平,等.蛋白酪氨酸磷酸酶自身抗体放射配体法的建立与临床应用.中华糖尿病杂志,2004,12(1)：18-20.
[13]黄干,周智广,彭健,等.35S标记重组人GAD65抗原检测糖尿病患者GAD-Ab指数.中华核医学杂志,2003,23(2)：82-86.
[14]王建平,周智广,黄干,等.IA-2A与GADA检测对1型糖尿病的诊断价值.中华内分泌代谢杂志,2004,12(6)：494-499.
[15]周卫东.1型糖尿病IL2B、SUM04、HLA-DQ基因多态性的关联分析及相互作用.[博士学位论文].长沙,中南大学,2008.
[16]Biason-Lauber A, Boehm B, Lang-Muritano M, et al. Association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity. Diabetologia,2005,48(5):900-905.
[17]Geng D. G., Liu S. Y., Steck A.et al.Comment on:Biason-Lauber A, Boehm B, Lang-Muritano M, et al (2005) Association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity. Diabetologia 48:900-905. Diabetologia,2006,49: 215-216
[18]张云,肖新华,王姮等.PAX4基因A1168C多态性与中国汉族人1型糖尿病的相关性.中国医学科学院学报,2007,29(3)：370-373.
[19]Hermann R, Mantere J, Lipponen K,et al. Lack of Association of PAX4 Gene With Type 1 Diabetes in the Finnish and Hungarian Populations. Diabetes,2005,54:2816-2819.
[20]Cheung WC, Kim JS, Linden M, et al. Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice. Journal of Clinical Investigation,2004,113:1763-1773.
[21]Donath MY & Halban PA. Decreased β-cell mass in diabetes:significance, mechanisms and therapeutic implications. Diabetologia 2004,47 581-589.
[22]Thierry Brun and Benoit R Gauthier. A focus on the role of Pax4 in mature pancreatic islet β-cell expansion and survival in health and disease. Journal of Molecular Endocrinology 2008,40:37-45
[23]Shimajiri Y,Shimabukuro M,Tomoyose T,et al. PAX4mutation(R121W)as a prodiabetic variant in Okinawans. Biochem Biophys Res Commun, 2003,302 (2):342-344.
[24]Nattachet Plengvidhya, Suwattanee Kooptiwut, Napat Songtawee, et al.PAX4 Mutations in Thais with Maturity Onset Diabetes of the Young. Clinic Endocri Metab,2006,92:2821-2826
[25]Maier LM, Cooper JD, Walker N,.et al. Comment to:Biason-Lauber A, Boehm B, Lang-Muritano M et al. (2005) association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity. Diabetologia 48:900-905. Diabetologia,2005,48: 2180-2182
[26]Gylvin T., Bergholdt R., Nerup. J.et al. To:Biason-Lauber A, Boehm B, Lang-Muritano M et al. Association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity. Diabetologia,2005,48:900-905
[27]Akey J, Jin L, Xiong M. Haplotypes vs single marker linkage disequilibrium tests:what do we gain? Eur J Hum Genet,2001,9:291-300.
[28]Zollner S, von Haeseler A. A coalescent approach to study linkage disequilubrium between singlenucleotide polymorphisms. Am J Hum Genet, 2000,66:615-628.
[1]Kitabchi AE. Ketosis-prone diabetes:a new subgroup of patients with atypical type 1 and type 2 diabetes? J Clin Endocrinol Metab,2003,88:5087-5089.
[2]Field LL. Genetic linkage and association studies of type 1 diabetes:challenges and rewards. Diabetologia,2002,45:21-35.
[3]Mauvais-Jarvis F,Smith SB,May CL,et al.PAX4 gene variations predispose to ketosis-prone diabetes. Human Molecular Genetics,2004,13:3151-3159.
[4]Yamada S, Motohashi Y,Yanagawa T,et al. NeuroD/BETA2 gene G→A Polymorphism May Affect Onset Pattern of Type 1 Diabetes in Japanese. Diabetes Care,2001,24:1438-1441
[5]Sohngwi E,Gautier JF,Riveline JP,et al. Ketosis-prone diabetes is associated to glucose-6-phosphate dehydrogenase deficiency in Afro-Caribbean patients(Abstract). Diabetes,2003,52(suppl.1):A356.
[6]Sobngwi E, Gautier JF, Kevorkian JP et al. High prevalence of glucose-6-phosphate dehydrogenase deficiency without gene mutation suggests a novel genetic mechanism predisposing to ketosis-prone diabetes. J Clin Endocrinol Metab 2005; 90:4446-4451.
[7]J.-F. Louet, S. B. Smith, J.-F. Gautier,et al.Gender and neurogenin3 influence the pathogenesis of ketosis-prone diabetes. Diabetes, Obesity and Metabolism, 2008,,10:912-920.
[8]张冬梅.特发1型糖尿病的临床特征和病因探讨[博士学位论文].长沙,中南大学,2003.
[9]Joel F. Habener, Daniel M. Kemp, and Melissa K. Thomas. Minireview: Transcriptional Regulation in Pancreatic Development. Endocrinology, 2005,146:1025-1034.
[10]German MS, Wang J, Chadwick RB, Rutter WJ. Synergistic activation of the insulin gene by a LIM-homeodomain protein and a basic helix-loop-helix protein:building a functional insulin minienhancer complex. Genes Dev 1992; 6: 2165-2176
[11]Kim JW, Seghers V, Cho JH, et al.Transactivation of the Mouse Sulfonylurea Receptor I Gene by BETA2/NeuroD. Mol Endocrinol,2002,16:1097-1107
[12]Copeman JB,Cucca F,Hearne CM,et al. Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene(IDDM7) to chromosome 2q31-q33. Nat Genet,1995,9:80-85.
[13]Apelqvist A, Li H, Sommer L, et al. Notch signalling controls pancreatic cell differentiation. Nature,1999,400:877-881.
[14]Ji Hyung Chae, Gretchen H. Stein, and Jacqueline E. Lee. NeuroD:The Predicted and the Surprising. Mol. Cells,2004,18, pp:271-288.
[15]Jensen J, Pedersen EE, Galante P, et al. control of endodermal development by Hes-1. Nat Genet,2000,24:36-44.
[16]Naya FJ,Huang HP,Qin Y,et al. Diabetes defective pancreatic morphogenesis, and abnormal enteroendocirine differentiation in BETA2/neuroD-deficient mice. Genes Dev 1997,11(18):2323-2334.
[17]Ondrej Cinek, Pavel Drevmek,Zdenek Summk, et al:NEUROD polymorphism Ala45Thr is associated with Type 1 diabetes mellitus in Czech children. Diabetes Research and Clinical Practice,2003,60:49-56.
[18]Lars Hansen, Jan N. Jensen, Sandra Urioste, et al:No Associations to Late-Onset Type 2 Diabetes but an A45 Allele May Represent a Susceptibility Marker for Type 1 Diabetes Among Danes. DIABETES,2000,49:876:879.
[19]Iwata I,Nagafuchi S,Nakashima H,et al. Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the Japanese. Diabetes,1999,48: 416-419.
[20]Dupont S,Vionnet N,Chevre JC,et al. No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD 1 and PAX4 in Type Ⅱ diabetes in France. Diabetologia,1999,42(4):480-484.
[21]MockizukiM, Amemiya S, Kobayashi K, et al.() The association of Ala45Thr polymorphism in NeuroD with child onset diabetes in Japanese.Diabetes Res Clin 2002,Pract 55:11-17.
[22]Malecki MT, Klupa T, Moczulski DK, et al. The Ala45thr polymorphism of BETA2/NeuroDl gene and susceptibility to type 1 diabetes mellitus in Caucasians. Exp Clin Endocrinol Diab,2003,111:251-254.
[23]Kavvoura F.K,.John Ioannidis P.A. Ala45Thr polymorphism of the NEUROD1 gene and diabetes susceptibility:a meta-analysis. Hum Genet,2005,116:192-199.
[24]Limei Liu, Weiping Jia, Taishan Zheng, et al. Ala45Thr variation in neuroD1 gene is associated with early-onset type 2 diabetes with or without diabetic pedigree in Chinese. Mol Cell Biochem,2006,290:199-204.
[25]Ye I, Xu Y, Zhu Y, et al. Association of polymorphism in neurogenic differentiation factor 1 gene with type 2 diabetes. Zhongua Yi Xue Yi Chuan Xue Za Zhi,2002,19:484-487.
[26]叶林秀,徐焱成,朱宜莲,等.1型糖尿病病人神经源分化因子NeuroD/BETA2基因多态性研究.中国糖尿病杂志,2003,11(3)：216-217.
[27]Iwata I,Nagafuchi S,Nakashima H,et al. Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the Japanese. Diabetes,1999,48: 416-419.
[28]Azuma Kanatsuka, Yoshiharu Tokuyama, Osamu Nozaki,et al.β Cell Dysfunction in Late-Onset Diabetic Subjects Carrying Homozygous Mutation in Transcription Factors NeuroD1 and Pax4. Metabolism,2002,51:1161-1165.
[29]Smith SB,Watada H,Scheel DW,et al. Autoregulation and maturity onset diabetes of the young transcription factots control the human PAX4 promoter[J]. J Biol Chem,2000,275(47):36910-36919.
[30]Brink C,Chowdhury K,Gruss P. Pax4 regulatory elements mediate beta cell specific expression in the pancreas. Mech Dev,2001,100 (1):37-43.
[31]唐迅,李娜,胡永华.应用多因子降维法分析基因-基因交互作用.中华流行病学杂志,2006,27(5)：437-441
[1]Kitabchi AE. Ketosis-prone diabetes:a new subgroup of patients with atypical type 1 and type 2 diabetes? J Clin Endocrinol Metab,2003,88:5087-5089.
[2]Mauvais-Jarvis F,Sobngwi E,Porcher R,et al.Ketosis-prone type 2 diabetes in patients of Sub-Saharan African origin:clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance. Diabetes,2004,53: 645-653.
[3]Mauvais-Jarvis F,Smith SB,May CL,et al.PAX4 gene variations predispose to ketosis-prone diabetes. Human Molecular Genetics,2004,13:3151-3159.
[4]Jonsson J, Carlsson L, Edlund T,et al. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature,1994,371:606-609.
[5]Offield MF, Jetton TL, Labosky PA,et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development,1996; 122:983-995.
[6]Harrison KA, Thaler J, Pfaff SL, et al. Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet,1999; 23:71-5.
[7]Li H, Arber S, Jessell TM,et al. Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9. Nat Genet,1999,23:67-70.
[8]M Sander, L Sussel, J Conners, et al. Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development,2000,127:5533-5540.
[9]Sussel, L, Kalamaras J, Hartigan-O'Connor DJ, et al. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development.1998,125:2213-2221.
[10]Ahlgren U, Pfaff SL, Jessell TM,et al. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells.Nature,1997,385:257-60.
[11]St-Onge L, Sosa-Pineda B, Chowdhury K,et al. Pax6 is required for differentiation of glucagon-producing-cells in mouse pancreas. Nature,1997, 387:406-409
[12]Sander M, Neubuser A, Kalamaras J,et al. Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev,1997,11:16621-673
[13]Sosa-Pineda B, Chowdhury K, Torres M,et al. The Pax4 gene is essential for differentiation of insulin-producing b cells in the mammalian pancreas. Nature, 1997,386:399-402.
[14]Naya,F.J. Huang H P,Qiu Y et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes & Dev.1997,11:2323-2334
[15]Huang, H.P. Chu K,Eric N G,et al. Neogenesis of beta-cells in adult BETA2/NeuroD-deficien mice. Mol. Endocrinol.2002,16:541-551.
[16]Gradwohl G.,Dierich A, LeMeur M,et al.. Neurogenin3 is required for the development of the endocrine cell lineages of the pancreas. Proc. Natl. Acad. Sci. USA,2000,97:1607-1611.
[17]Gu G., Brown J.R., Melton D.A. Direct lineage tracing reveals the ontoge of pancreatic cell fates during mouse embryogenesis. Mech. Dev.2003,120: 35-43.
[18]Lee Y.H., Sauer B., Gonzalez F.J.. Laron dwarfism and non-insulin-dependent diabetes mellitus in the Hnf-lalpha knockout mouse. Mol. Cell Biol.1998,18: 3059-3068.
[19]Pontoglio M, Barra J, Hadchouel M,. et al. Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice. J. Clin. Invest.1998,101: 2215-2222.
[20]Kaestner K.H., The hepatocyte nuclear factor 3 (HNF3 or FOXA) family inmetabolism. Trends Endocrinol. Metab.2000,11:281-285.
[21]Swarup K. Chakrabartil and Raghavendra G. Mirmira.Transcription factors direct the development and function of pancreatic β cells. Trends Endocrinol. Metab.2003,14:78-85.
[22]Pilz, A. J., Povey, S., Gruss, P.; et al. Mapping of the human homologs of the murine paired-box-containing genes. Mammalian Genome,1993,4:78-82.
[23]Tamura. T., Izumikawa. Y., Kishino. T., et al. Assignment of the human PAX4 gene to chromosome band 7q32 by fluorescence in situ hybridization. Cytogenet Cell Genet.,1994,66:132-134.
[24]Sosa-Pineda B,Chowdhury K,Torres M,et al. The Pax4 gene is essential for diferentiation of insulin-producing beta cells in the mammalian pancreas Nature, 1997,386:399-402.
[25]J.M.Servitja, J.Ferrer, Transcriptional networks controlling pancreatic development and beta cell function.Diabetologia,2004,47:597-613.
[26]Smith S, Ee H, Conners J,et al. Paired-homeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development. Molecular and Cellular Biology,1999,19:8272-8280.
[27]Smith SB, Watada H, Scheel DW, et al. Autoregulation and maturity onset diabetes of the young transcription factors control the human PAX4 promoter. Journal of Biological Chemistry,2000,275:36910-36919.
[28]Sosa-Pineda B, Chowdhury K, Torres M, et al. The Pax4 gene is essential for differentiation of insulin-producing P cells in the mammalian pancreas. Nature,1997,386:399-402.
[29]Zhang YQ, Mashima H & Kojima I. Changes in the expression of transcription factors in pancreatic AR42J cells during differentiation into insulin-producing cells. Diabetes,2001,50:S10-S14.
[30]Heremans Y, Van De Casteele M, in't Veld P,et al. Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3. Journal of Cell Biology,2002,159:303-312.
[31]Kojima H, Fujimiya M, Matsumura K, et al. NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nature Medicine,2003,9:596-603.
[32]Theis M, Mas C, Doring B, et al. Replacement by a lacZ reporter gene assigns mouse connexin 36,45 and 43 to distinct cell types in pancreatic islets. Experimental Cell Research 2004,294:18-29.
[33]St-Onge L, Sosa-Pineda B, Chowdhury K, et al. Pax6 is required for differentiation of glucagon-producing a-cells in mouse pancreas. Nature. Smith SB,Watada H,Scheel DW,et al. Autoregulation and maturity onset diabetes of the young transcription factots control the human PAX4 promoter. J Biol Chem,2000,275:36910-36919.
[34]Brink C,Chowdhury K,Gruss P. Pax4 regulatory elements mediate beta cell specific expression in the pancreas. Mech Dev,2001,100:37-43.
[35]Kemp DM,Lin JC,Habener JF. Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer factor. J Biol Chem.2003;278:35057-62
[36]Fujitani Y,Kajimoto Y,Yasuda T,et al. Identification of a portable repression domain and an E1A-responsive activation domain in Pax4:a possible role of Pax4 as a transcriptional repressor in the pancreas. Mol. Cell. Biol.,1999, 19:8281-8291.
[37]Campbell SC,Cragg H, Elrick LJ et al.Inhibitory effect of pax4 on the human insulin and isleta myloid polypeptide(IAPP) promoters. FEBS Lett,1999,10: 53-57.
[38]Holm P, Rydlander B, Luthman H, et al. Interaction and association analysis of a type 1 diabetes susceptibility locus on chromosome 5q11-q13 and the 7q32 chromosomal region in Scandinavian families. Diabetes,2004,53:15842-15911.
[39]Blyszczuk P,Czyz J,Kania G,et al. Expression of Pax4 in embryonic stem cells promotes diferentiation of nestin-positive progenitor and insulin-producing cells. Proc Natl Acad Sci USA,2003,100 (3):998-1003.
[40]Biason-Lauber A, Boehm B, Lang-Muritano M, et al. Association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity. Diabetologia,2005,48(5):900-905.
[41]Hermann R, Mantere J, Lipponen K,et al. Lack of Association of PAX4 Gene With Type 1 Diabetes in the Finnish and Hungarian Populations. Diabetes 2005,54:2816-2819.
[42]Geng D. G., Liu S. Y., Steck A.et al.Comment on:Biason-Lauber A, Boehm B, Lang-Muritano M, et al (2005) Association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerativecapacity. Diabetologia 48:900-905. Diabetologia,2006,49:215-216
[43]Gylvin T, Bergholdt R, Nerup J, et al. To:Biason-Lauber A, Boehm B, Lang-Muritano M et al. association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity.Diabetologia, 2005,48 (10):2183-2184
[44]张云,肖新华,王姮,等.PAX4基因A1168C多态性与中国汉族人1型糖尿病的相关性.中国医学科学院学报,2007,29(3)：370-373.
[45]Shimajiri Y, Sanke T, Furuta H, et al. A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese.. Diabetes,2001,50: 2864-2869.
[46]Shimajiri Y,Shimabukuro M,Tomoyose T,et al. PAX4 mutation(R121W)as a prodiabetic variant in Okinawans. Biochem Biophys Res Commun,2003,302 (2): 342-344.
[47]Dupont S,Vionnet N,Chevre JC,et al. No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in Type Ⅱ diabetes in France. Diabetologia,1999,42(4):480-484.
[48]Tao T, Wasson J, Bemal-Mizrachi E, et al. Isolation and characterization of the human PAX4 gene.Diabetes,1998,47:1650-1653
[49]Mauvais-Jarvis F,Smith SB,Le May C,et al. PAX4 gene variations predispose to ketosis-prone diabetes. Hum Mol Genet,2004,13 (24):3151-3159.
[50]Apelqvist A, Li H, Sommer L, et al. Notch signalling controls pancreatic cell differentiation. Nature,1999,400:877-881.
[51]Jensen J, Pedersen EE, Galante P, et al. control of endodermal development by Hes-1. Nat Genet,2000,24:36-44.
[52]Naya FJ,Huang HP,Qin Y,et al. Diabetes defective pancreatic morphogenesis, and abnormal enteroendocirine differentiation in BETA2/neuroD-deficient mice[J]Genes Dev 1997,11(18):2323-2334.
[53]Malecki MT,Jhala US,Antonellis A,et al. Mutation in Neurod 1 are associated with the development of type 2 diabetes meilitus. Nature Genetics,1999,23: 323-328.
[54]Kristinsson SY,Thorolfsdottir ET,Talseth B,et at. MODY in Iceland is associated with mutations in HNF-1a and a novel mutation in NeuroD1. Diabetologia,2001, 44:2098-2103.
[55]Limei Liu, Weiping Jia, Taishan Zheng, et al. Ala45Thr variation in neuroD1 gene is associatedwith early-onset type 2 diabetes with or without diabetic pedigree in Chinese. Molecular and Cellular Biochemistry,2006,290:199-204.
[56]Kanatsuka A,Tokuyama Y,Nozaki O,et al.Beta-cell dysfunction in subjects carrying homozygous mutation in transcription factors Neurod1 and Pax4. Metabolism,2002,51:1161-1165.
[57]Copeman JB,Cucca F,Hearne CM,et al. Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene(IDDM7) to chromosome 2q31-q33. Nat Genet,1995,9:80-85.
[58]Iwata I,Nagafuchi S,Nakashima H,et al. Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the Japanese. Diabetes,1999,48: 416-419.
[59]Lars Hansen, Jan N. Jensen, Sandra Urioste, et al:No Associations to Late-Onset Type 2 Diabetes but an A45 Allele May Represent a Susceptibility Marker for Type 1 Diabetes Among Danes. DIABETES,2000,49:876-879.
[60]Malecki MT,Cyganek K,Klupa T,et al. The Ala45Thr polymorphism of BETA2 /NeuroDl gene and susceptibility to type 2 diabetes mellitus in a Polish population. Acta Diabetol,2003,40:109-111.
[61]Mochizuki M,Amemiya S,Kobayashi K,et al. The association of Ala45Thr polymorphism in NeuroD with child-onset Type 1a diabetes in Japanese. Diabetes Res Clin Pract,2002,55:11-17.
[62]Satoru Yamada,Yoshko Motohashi,Tatsuo Yanagawa, et al. NeuroD/BETA2 Gene G→A Polymorphism May Affect Onset Pattern of Type 1 Diabetes in Japanese. Diabetes Care,2001,24:1438-1441.
[63]Ondrej Cinek, Pavel Drevmek,Zdenek Summk, et al:NEUROD polymorphism Ala45Thr is associated with Type 1 diabetes mellitus in Czech children. Diabetes Research and Clinical Practice,2003,60:49-56.
[64]S.Dupont,N.Vionnet, J.C.Ch.vre, et al:No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in Type II diabetes in France. Diabetologia,1999,42:480-484.
[65]Takuya Awata,Kiyoaki Inoue,Ikuo Inoue,et al:Lack of association of the Ala45Thr variant in theBETA2:NEUROD1 with type 1 diabetes in Japanese. Diabetes Research and Clinical Practice,2000,49:61-63.
[66]韩学尧,刘春雁,纪立农.MODY6基因在家族性2型糖尿病发病中的作用中华医学杂志,2005,85(35)：2463-2467.
[67]叶林秀,徐焱成,朱宜莲,等.1型糖尿病病人神经源分化因子NeuroD/BETA2基因多态性研究.中国糖尿病杂志,2003,11(3)：216-217.
[68]Baumhueter S, Mendel DB, Conley PB,et al:HNF-1 shares three sequence motifs with the POU domain proteins and is identical to LF-B1 and APF. Genes Dev,1990,4:372-379.
[69]Bach, I., Galcheva-Gargova, Z., Mattei, M.-G.,et al. Cloning of human hepatic nuclear factor 1 (HNF1) and chromosomal localization of its gene in man and mouse. Genomics,1990,8:155-164.
[70]Yamagata K, Oda N, Kaisaki PJ,et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature, 1996,384:455-458.
[71]Winter WE,Nakamura M,House DV. Monogenic diabetes mellitus in youth.The MODY syndromes. Endocrinol Metab Clin North AM,1999,28:765-785.
[72]Yanuka Kashles O,Cohen H,Cihail T,et al. Transcriptional regulation of the Phosphoenolpyruvate carboxykinase gene by cooperation between hepatic nuclear factors. Mol Cell Biol,1994,14:7124-7133.
[73]Menzel R,Kaisaki PJ,Rjasanowski I,et al. A low renal threshold for glucose in diabetic patients with a mutation in the hepatocyte nuclear factor-1 alpha(HNF-lalpha) gene. Diabet Med,1998,15:816-820.
[74]Pontoglio M, Barra J, Hadchouel M, et al. Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell,1996,84(4):575-85.
[75]Pontoglio M, Sreenan S, Roe M, et al. Defective insulin secretion in hepatocyte nuclear factor 1 alpha-deficient mice. J Clin Invest,1998,101:2215-2222.
[76]Boj SF, Parrizas M, Maestro MA,et al. A transcription factor regulatory circuit in differentiated pancreatic cells. Proc Natl Acad Sci USA,2001,98: 14481-14486.
[77]Shih DQ, Screenan S, Munoz KN et al. Loss of HNF-lalpha function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism. Diabetes,2001,50:2472-2480.
[78]Farrelly AM, Wobser H, Bonner C,et al. Early loss of mammalian target of rapamycin complex 1 (mTORC1) signalling and reduction in cell size during dominant-negative suppression of hepatic nuclear factor 1-alpha(HNF1A) function in INS-1 insulinoma cell. Diabetologia.2009,52(1):136-44.
[79]Finegood, D. T., Scaglia, L.,et al. Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes,1995,44: 249-256.
[80]Ferrer J. A genetic switch in pancreatic beta-cells:implications for differentiation and haploinsufficiency. Diabetes,2002,51:2355-2362.
[81]Stoffel M, Duncan SA. The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci USA,1997,94: 13209-13214.
[82]Vaxillaire M, Abderrahmani A, Boutin P et al. Anatomy of a homeoprotein revealed by the analysis of human MODY3 mutations. J Biol Chem,1999,274: 35639-35646.
[83]Hansen SK, Parrizas M, Jensen ML et al. Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function. J Clin Invest,2000,110:827-833.
[84]Thomas H, Badenberg B, Bulman M et al. Evidence for haploinsufficiency of the human HNF1alpha gene revealed by functional characterization of MODY3-associated mutations. Biol Chem,1998,383:1691-1700.
[85]Gragnoli C, Lindner T, Cockburn BN et al. Maturity-onset diabetes of the young due to a mutation in the hepatocyte nuclear factor-4 alpha binding site in the promoter of the hepatocyte nuclear factor-1 alpha gene.Diabetes,1997,46: 1648-1651.
[86]Moller AM,Dalgaard LT,Pociot F,et al. Mutation in the hepatocyte nuclear factor-1 alpha gene in Caucasian families originally classified as having Typel diabetes. Diabetologia,1998,41:1528-1531.
[87]Yamada, S., Nishigori, H., Onda, H.,et al. Identification of mutations in the hepatocyte nuclear factor (HNF)-1-alpha gene in Japanese subjects with IDDM. Diabetes,1997,46:1643-1647.
[88]Yoshiuchi, I., Yamagata, K.;,Yoshimoto, M.,et al. Analysis of a non-functional HNF-1-alpha (TCF1) mutation in Japanese subjects with familial type 1 diabetes. Hum. Mutat.2001,18:345-351.
[89]Yoshiuchi, I., Yamagata, K.,Yang Q,et al. Three new mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with diabetes mellitus:clinical features and functional characterization. Diabetologia,1999,42:621-626.
[90]Kawasaki E,Sera Y,Yamakawa K,et al. Identification and functional analysis of mutation in the hepatocyte nuclear factor-1alpha gene in anti-islet autoantibody-negativeJapanese patients with type 1 diabetes. J Clin Endocrinal Metab,2000,85:331-335.
[91]Byrne M. M.,Sturis J.,Menzel S.,et al. Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Diabetes,1996,45: 1503-1510.
[92]Yamagata K., Oda N., Kalsaki P. J.,et al. Mutations in the hepatocyte nuclear factor-1-alpha gene in maturity-onset diabetes of the young (MODY3). Nature, 1996,384:455-457.
[93]Kaisaki P. J., Menzel S., Lindner T.,et al. Mutations in the hepatocyte nuclear factor-1-alpha gene in MODY and early-onset NIDDM:evidence for a mutational hotspot in exon 4. Diabetes,1997,46:528-535.
[94]韩学尧,纪立农.MODY3基因在早发家族性2型糖尿病发病中的作用.中国糖尿病杂志,2007,15(3)：153-155.
[95]方启晨,张蓉,王从容,等.中国人早发及多发糖尿病家系HNF-1α基因突变的筛查.中华医学遗传学杂志,2004,21(4)：329-334.
[96]Chiu K.C.,Chuang L.M., Ryu J. M.,et al. The I27L amino acid polymorphism of hepatic nuclear factor-1-alpha is associated with insulin resistance. J. Clin. Endocr. Metab.,2000,85:2178-2183.
[97]Babaya, N.; Ikegami, H.; Fujisawa, T.;et al. Association of I27L polymorphism of hepatocyte nuclear factor-1-alpha gene with high-density lipoprotein cholesterol level. J. Clin. Endocr. Metab.,2003,88:2548-2551.
[98]Hegele, R. A.; Cao, H.; Harris, S. B.;et al. The hepatic nuclear factor-1-alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. J. Clin. Endocr. Metab,1999,84:1077-1082.
[99]Triggs-Raine, B. L.; Kirkpatrick, R. D.; Kelly, S. L.;et al. HNF1-alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community. Proc. Nat. Acad.Sci.,2002,99:4614-4619.
[100]马立隽,卞茸文,王华,等.中国人MODY/NIDDM家系葡萄糖激酶和肝细胞核因子1α基因缺陷的分子筛查.中华内分泌代谢杂志,2003,19(3)：216-220.
[2]Mauvais-Jarvis F, Sobngwi E, Porcher R; et al. Ketosis-prone type 2 diabetes in patients of sub-Saharan African origin:clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance.Diabetes.2004;53(3): 645-653.
[3]Kitabchi AE. Ketosis-prone diabetes-a new subgroup of patients with atypical type 1 and type 2 diabetes? J Clin Endocrinol Metab.2003;88(11):5087-5089.
[4]Maldonado MM, Hampe CS, Gaur LK,et al. Ketosis-prone diabetes:dissection of a heterogeneous syndrome using an immunogenetic and β-cell functional classification, prospective analysis,and clinical outcomes. J Clin Endocrinol Metab,2003,88:5090-5098.
[5]周智广,张弛,张冬梅等.特发1型糖尿病的临床特征及其亚型诊断探讨.中华糖尿病杂志,2004,12(2)：79-85
[6]张驰.酮症倾向糖尿病的异质性及分型诊断研究.[博士学位论文].长沙,中南大学,2005.
[7]张冬梅,周智广,胡白瑛,等.自发酮症起病的肥胖糖尿病患者临床特征和分型探讨.中华内分泌代谢杂志,2003,19(3)：221-224
[8]Mauvais-Jarvis F,Smith SB,May CL,et al.PAX4 gene variations predispose to ketosis-prone diabetes. Human Molec Genet,2004,13:3151-3159.
[9]Sohngwi E,Gautier JF,Riveline JP,et al. Ketosis-prone diabetes is associated to glucose-6-phosphate dehydrogenase deficiency in Afro-Caribbean patients (Abstract). Diabetes,2003,52(suppl.1):A356.
[10]Sohngwi E,Gautier JF,Kevorkian JP,et al. High prevalence of glucose-6-phosphate dehydrogenase deficiency without gene mutation suggests a novel genetic mechanism predisposing to ketosis-prone diabetes. Clin Endocrinol Metab.2005,90(8):4446-51
[11]Sobngwi E,Choukem SP,Agbalika F,et al. Ketosis-prone type2 diabetes mellitus and human Herpesvirus 8 infection in Sub-Saharan Africans. JAMA,2008, 299(23):2770-2776.
[12]D.Zhang, Z.Zhou, L. Li,et al.Islet autoimmunity and genetic mutations in Chinese subjects initially thought to have Type 1B diabetes. Diabetic Medicine, 2005,23,67-71
[13]Banerji MA,Chaiken RL,Huey H,et al. GAD antibody negative NIDDM in adult black subjects with diabetic ketoacidosis and increased frequency of human leukocyte antigen DR3 and DR4.Flatbush diabetes. Diabetes,1994,43:741-745.
[14]Davis TM,Zimmet P,Davis WA,et al. Autoantibodies to glutamic acid decardoxylase in diabetic patients from a multi-ethnic Austrlian community:the Fremantle Diabetes Study. Diabet Med,2000,17:667-674.
[15]Todd AL,Ng WY,Lui KF,et al. Low prevalence of autoimmune diabetes markers in a mixed ethnic population of Singaporean diabetics. Intern Med J,2004,34:24-30
[16]Sosa-Pineda B, Chowdhury K, Torres M,et al. The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas. Nature, 1997,386:399-402.
[17]Yoshinori S, Tokio S, Hiroto F,et al. A Missense Mutation of Pax4 Gene (R121W) Is Associated With Type 2 Diabetes in Japanese. Diabetes, 2001,50:2864-2869,
[18]Dupont S, Vionnet N, Chevre JC,et al. No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in Type Ⅱ diabetes in France. Diabetologia,1999,42(4):480-4.
[19]Winter WE,Nakamura M,House DV. Monogenic diabetes mellitus in youth. The MODY syndromes. Endocrinol Metab Clin North AM,1999,28(4):765-85.
[20]Dumonteil E, Philippe J. Insulin gene:organization,expression and regulation. Diabete Metab,1996,22:164-173.
[21]Kim JW, Seghers V,Cho JH,et al. Transactivation of the miuse sulfonylurea receptor 1 gene by BETA2/NeuroD. Mol Endocrinol,2002,16:1097-1107.
[22]Naya FJ, Huang HP, Qiu Y,et al. Diabete,defective pancreatic morphogenesis,and abnormal enteroendocrine differentiation in BETA2/NeuroD-deficient mice. Genes.Dev,1997,11(18):2323-2334.
[23]Huang HP, Chu K,Nemoz-Gaillard E,et al, Neogenesis of beta-cells in adult BETA2/NeuroD-deficient mice. Mol Endocrinol,2002,16(3):541-551.
[24]Hansen L. Candidate gene and late-onset type 2 diabetes mellitus:Susceptibility genes or common polymorphism? Dan Med Bull,2003,50:320-346.
[25]Malecki MT, Klupa T, Moczulski DK,et al. The Ala45Thr polymorphism of BETA2/NeuroD1 gene and susceptibility to type 1 diabetes mellitus in caucasians. Exp Clin Endocrinol Diabetes.2003;111(5):251-4.
[26]Iwata I, Nagafuchi S, Nakashima H,et al. Association of polymorphism in the NeuroD1/Beta2 gene with Type 1 diabetes in the Japanese. Diabetes,1999, 48(2):416-419
[27]Yamada S, Motohashi Y, Yanagawa T,et al. NeuroD1/Beta2 gene C→A polymorphism may affect onset pattern of type1 diabetes in Japanese. Diabetes Care,2001,24:1438-1441.
[28]Dupont S, Dina C, Hani EH, et al. Absence of replication in the French population of the association between beta 2/NEUROD-A45T polymorphism and type 1 diabetes. Diabetes Metab 1999,25:516-517.
[29]Awata T, Inoue K, Inoue I, et al. Lack of association of the Ala45Thr variant in the NeuroD/BETA2 with type 1 diabetes in Japanese. Diab Res Clin Pract.2000,49:61-63
[30]徐焱成,叶林秀,朱宜莲,等.神经源分化因子基因多态性与2型糖尿病的关联性研究.中华医学遗传学杂志,2002,19(6)：484-487
[31]Limei Liu, Weiping Jia, Taishan Zheng,et al.Ala45Thr variation in neuroDl gene is associated with early-onset type 2 diabetes with or without diabetic pedigree in Chinese. Mol Cell.Bioche.2006,290:199-204.
[32]叶林秀,徐焱成,朱宜莲,等.1型糖尿病病人神经源分化因子NeuroD/BETA2基因多态性研究.中国糖尿病杂志,2003,11(3)：216-217
[1]Umpierrez GE, Woo W, Hagopian WA, Isaacs SD, Palmer JP, Gaur LK, et al. Immunogenetic analysis suggests different pathogenesis for obese and lean African-Americans with diabetic ketoacidosis. Diabetes Care.1999;22:1517-23.
[2]Mauvais-Jarvis F, Sobngwi E, Porcher R, et al. Ketosis-prone type 2 diabetes in patients of sub-Saharan African origin:clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance. Diabetes.2004;53: 645-53.
[3]Ashok Balasubramanyam, Gilberto Garza, Lucille Rodriguez,et al. Accuracy and Predictive Value of Classification Schemes for Ketosis-Prone Diabetes. Diabetes Care,2006,29:2575-2579
[4]Maldonado MM,Hampe CS,Gaur LK,et al.Ketosis-prone diabetes:dissection of a heterogeneous syndrome using an immunogenetic and β-cell functional classification, prospective analysis, and clinical outcomes. J Clin Endocrinol Metab,2003,88:5090-5098.
[5]Imagawa A,Hanafusa T,Uchigata Y,et al. Different contribution of class Ⅱ HLA in fulminant and typical autoimmune type 1 diabetes mellitus. Diabetologia, 2005,48:294-300
[6]周智广,张驰,张冬梅等.特发1型糖尿病的临床特征及其亚型诊断探讨.中华内糖尿病杂志,2004,12(2)：79-85
[7]Sosa-Pineda B, Chowdhury K, Torres M,et al. The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas. Nature, 1997,386:399-402.
[8]Biason-Lauber A, Boehm B, Lang-Muritano M, et al. Association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity. Diabetologia,2005,48:900-905
[9]Hermann R, Mantere J, Lipponen K,et al. Lack of Association of PAX4 Gene With Type 1 Diabetes in the Finnish and Hungarian Populations. Diabetes 2005,54:2816-2819
[10]Yoshinori S,Tokio S,Hiroto F,et al. A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese. Diabetes,2001,50:2864-2869.
[11]Yoshiharu Tokuyama, Kana Matsui, Toshiharu Ishizuka,et al. The Arg121Trp variant in PAX4 gene is associated with beta-cell dysfunction in Japanese subjects with type 2 diabetes mellitus. Metabolism,2006,55(2):213-216
[12]Mauvais-Jarvis F,Smith SB,May CL,et al.PAX4 gene variations predispose to ketosis-prone diabetes. Human Molecular Genetics,2004,13:3151-3159.
[13]Nattachet Plengvidhya, Suwattanee Kooptiwut, Napat Songtawee,et al. PAX4 Mutations in Thais with Maturity Onset Diabetes of the Young. The Journal of Clinical Endocrinology & Metabolism.2007,92(7):2821-2826
[14]张云,肖新华,王姮等.PAX4基因A1168C多态性与中国汉族人1型糖尿病的相关性.中国医学科学院学报,2007,29(3)：370-373
[15]Xiao W., Oefner. P.J. Denaturing high-performance liquid chromatography:A review. Hum Mutat,2001,17(6):439-74
[16]Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care,2001,24:131-15
[17]黄干,周智广,彭健,等.35S标记重组人GAD65抗原检测糖尿病患者GAD-Ab指数.中华核医学杂志,2003,23：82-86.
[18]萨姆布鲁克J,弗里奇EF,曼尼阿蒂斯T.分子克隆实验指南(金冬雁译).第二版．北京：科学出版社,1992.
[19]Taliani MR,Roberts SC,Dukek BA,et al. Sensitivity and specificity of denaturing high-pressure liquid chromatography for unknown protein C gene mutations. Genet Test.2001,Spring;5(1):39-44.
[20]Oefner PJ,Underhill PA. Comparative DNA sequencing by denaturing high-performance liquid chromatography(DHPLC). Am J Hum Genet,1995, 57:A266.
[21]Spiegelman JI,Mindrins MN,Oefner PJ. High accuracy DNA sequence variation screening by DHPLC. BioTechniques 2000,29(5):1084-1092.
[22]O'Donovan M C,Oefner P J,Roberts S,et al. Blind analysis of denaturing high performance liquid chromatography as a tool for mutation detection. Genomics, 1998,52(1):44-49.
[23]Jones A C, Austin J,Hansen N,et al. Optimal temperature selection for mutation detection by denaturing HPLC and comparison to single-stranded conformation polymorphism and fieteroduplex analysis.Clin. Chem.1999,45(8 Pt 1): 1133-1140.
[24]Gross E,Arnold N,Pfeifer K,et al. Identification of specific BRCA1 and BRCA2 variants by DHPLC. Hum. Mutat.2000,16(4):345-353.
[25]Jiang WY,Chen LM,Lin QD,et al. Denaturing high-performance liquid chromatography technique platform applied to screen G6PD deficient variants. Zhonghua Yi Xue Yi Chuan Xue Za Zhi,2005,22(6):607-611.
[26]Rachel Howarth Catharina Yearwood John F. Harvey. Application of dHPLC for Mutation Detection of the Fibrillin-1 Gene for the Diagnosis of Marfan Syndrome in a National Health Service Laboratory. Genetic Testing,2007,11(2):146-152
[27]吴柏林,朱建中.变性高效液相色谱基因扫描技术在人类疾病基因诊断中的应用.中华医学遗传学杂志,2004,21(5)：
[28]韩伟,楼定华,王竞,等.变性高效液相色谱分析法在人类基因组单核苷酸多态性检测中的应用.浙江大学学报(医学版),2005,34(3)：248-254
[1]Balasubramanyam AGG, Rodriguez L, Hampe C, et al:Accuracy and predictive value of classification schemes for ketosis-prone diabetes mellitus (KPDM). Diabetes Care,2006,29:2575-2579
[2]Imagawa A,Hanafusa T,Uchigata Y,et al. Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus. Diabetologia,2005,48:294-300
[3]周智广,张驰,张冬梅等.特发1型糖尿病的临床特征及其亚型诊断探讨.中华内糖尿病杂志,2004,12(2)：79-85
[4]Mauvais-Jarvis F,Sobngwi E,Porcher R,et al.Ketosis-prone type 2 diabetes in patients of Sub-Saharan African origin:clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance. Diabetes,2004,53:645-653.
[5]Mauvais-Jarvis F,Smith SB,May CL,et al.PAX4 gene variations predispose to ketosis-prone diabetes. [J]. Human Molecular Genetics,2004,13: 3151-3159.
[6]Sosa-Pineda, B., K. Chowdhury, M. Torres, et al. The Pax4 gene is essential for differentiation of insulin-producing beta cells in the mammalian pancreas. Nature.1997,386:399-402.
[7]Holm P, Rydlander B, Luthman H, et al. Interaction and association analysis of a type 1 diabetes susceptibility locus on chromosome 5q11-q13 and the 7q32 chromosomal region in Scandinavian families. Diabetes, 2004,53:1584-1591
[8]Thierry Brun, Isobel Franklin, Luc St-Onge,et al. The diabetes-linked transcription factor PAX4 promotes β-cell proliferation and survival in rat and human islets. JCB,2004,167(6):1123-1135
[9]Mauvais-Jarvis F,Smith SB,Le May C,et al. PAX4 gene variations predispose to ketosis-prone diabetes. Hum Mol Genet,2004,13 (24): 3151-3159.
[10]Shimajiri Y, Sanke T, Furuta H, et al. A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese.. Diabetes,2001,50: 2864-2869.
[11]王建明,周智广,文建新,等.谷氨酸脱羧酶(GAD65)自身抗体的放射配体法.中国糖尿病杂志,1997,5(2)：85-88.
[12]黄干,周智广,王建平,等.蛋白酪氨酸磷酸酶自身抗体放射配体法的建立与临床应用.中华糖尿病杂志,2004,12(1)：18-20.
[13]黄干,周智广,彭健,等.35S标记重组人GAD65抗原检测糖尿病患者GAD-Ab指数.中华核医学杂志,2003,23(2)：82-86.
[14]王建平,周智广,黄干,等.IA-2A与GADA检测对1型糖尿病的诊断价值.中华内分泌代谢杂志,2004,12(6)：494-499.
[15]周卫东.1型糖尿病IL2B、SUM04、HLA-DQ基因多态性的关联分析及相互作用.[博士学位论文].长沙,中南大学,2008.
[16]Biason-Lauber A, Boehm B, Lang-Muritano M, et al. Association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity. Diabetologia,2005,48(5):900-905.
[17]Geng D. G., Liu S. Y., Steck A.et al.Comment on:Biason-Lauber A, Boehm B, Lang-Muritano M, et al (2005) Association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity. Diabetologia 48:900-905. Diabetologia,2006,49: 215-216
[18]张云,肖新华,王姮等.PAX4基因A1168C多态性与中国汉族人1型糖尿病的相关性.中国医学科学院学报,2007,29(3)：370-373.
[19]Hermann R, Mantere J, Lipponen K,et al. Lack of Association of PAX4 Gene With Type 1 Diabetes in the Finnish and Hungarian Populations. Diabetes,2005,54:2816-2819.
[20]Cheung WC, Kim JS, Linden M, et al. Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice. Journal of Clinical Investigation,2004,113:1763-1773.
[21]Donath MY & Halban PA. Decreased β-cell mass in diabetes:significance, mechanisms and therapeutic implications. Diabetologia 2004,47 581-589.
[22]Thierry Brun and Benoit R Gauthier. A focus on the role of Pax4 in mature pancreatic islet β-cell expansion and survival in health and disease. Journal of Molecular Endocrinology 2008,40:37-45
[23]Shimajiri Y,Shimabukuro M,Tomoyose T,et al. PAX4mutation(R121W)as a prodiabetic variant in Okinawans. Biochem Biophys Res Commun, 2003,302 (2):342-344.
[24]Nattachet Plengvidhya, Suwattanee Kooptiwut, Napat Songtawee, et al.PAX4 Mutations in Thais with Maturity Onset Diabetes of the Young. Clinic Endocri Metab,2006,92:2821-2826
[25]Maier LM, Cooper JD, Walker N,.et al. Comment to:Biason-Lauber A, Boehm B, Lang-Muritano M et al. (2005) association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity. Diabetologia 48:900-905. Diabetologia,2005,48: 2180-2182
[26]Gylvin T., Bergholdt R., Nerup. J.et al. To:Biason-Lauber A, Boehm B, Lang-Muritano M et al. Association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity. Diabetologia,2005,48:900-905
[27]Akey J, Jin L, Xiong M. Haplotypes vs single marker linkage disequilibrium tests:what do we gain? Eur J Hum Genet,2001,9:291-300.
[28]Zollner S, von Haeseler A. A coalescent approach to study linkage disequilubrium between singlenucleotide polymorphisms. Am J Hum Genet, 2000,66:615-628.
[1]Kitabchi AE. Ketosis-prone diabetes:a new subgroup of patients with atypical type 1 and type 2 diabetes? J Clin Endocrinol Metab,2003,88:5087-5089.
[2]Field LL. Genetic linkage and association studies of type 1 diabetes:challenges and rewards. Diabetologia,2002,45:21-35.
[3]Mauvais-Jarvis F,Smith SB,May CL,et al.PAX4 gene variations predispose to ketosis-prone diabetes. Human Molecular Genetics,2004,13:3151-3159.
[4]Yamada S, Motohashi Y,Yanagawa T,et al. NeuroD/BETA2 gene G→A Polymorphism May Affect Onset Pattern of Type 1 Diabetes in Japanese. Diabetes Care,2001,24:1438-1441
[5]Sohngwi E,Gautier JF,Riveline JP,et al. Ketosis-prone diabetes is associated to glucose-6-phosphate dehydrogenase deficiency in Afro-Caribbean patients(Abstract). Diabetes,2003,52(suppl.1):A356.
[6]Sobngwi E, Gautier JF, Kevorkian JP et al. High prevalence of glucose-6-phosphate dehydrogenase deficiency without gene mutation suggests a novel genetic mechanism predisposing to ketosis-prone diabetes. J Clin Endocrinol Metab 2005; 90:4446-4451.
[7]J.-F. Louet, S. B. Smith, J.-F. Gautier,et al.Gender and neurogenin3 influence the pathogenesis of ketosis-prone diabetes. Diabetes, Obesity and Metabolism, 2008,,10:912-920.
[8]张冬梅.特发1型糖尿病的临床特征和病因探讨[博士学位论文].长沙,中南大学,2003.
[9]Joel F. Habener, Daniel M. Kemp, and Melissa K. Thomas. Minireview: Transcriptional Regulation in Pancreatic Development. Endocrinology, 2005,146:1025-1034.
[10]German MS, Wang J, Chadwick RB, Rutter WJ. Synergistic activation of the insulin gene by a LIM-homeodomain protein and a basic helix-loop-helix protein:building a functional insulin minienhancer complex. Genes Dev 1992; 6: 2165-2176
[11]Kim JW, Seghers V, Cho JH, et al.Transactivation of the Mouse Sulfonylurea Receptor I Gene by BETA2/NeuroD. Mol Endocrinol,2002,16:1097-1107
[12]Copeman JB,Cucca F,Hearne CM,et al. Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene(IDDM7) to chromosome 2q31-q33. Nat Genet,1995,9:80-85.
[13]Apelqvist A, Li H, Sommer L, et al. Notch signalling controls pancreatic cell differentiation. Nature,1999,400:877-881.
[14]Ji Hyung Chae, Gretchen H. Stein, and Jacqueline E. Lee. NeuroD:The Predicted and the Surprising. Mol. Cells,2004,18, pp:271-288.
[15]Jensen J, Pedersen EE, Galante P, et al. control of endodermal development by Hes-1. Nat Genet,2000,24:36-44.
[16]Naya FJ,Huang HP,Qin Y,et al. Diabetes defective pancreatic morphogenesis, and abnormal enteroendocirine differentiation in BETA2/neuroD-deficient mice. Genes Dev 1997,11(18):2323-2334.
[17]Ondrej Cinek, Pavel Drevmek,Zdenek Summk, et al:NEUROD polymorphism Ala45Thr is associated with Type 1 diabetes mellitus in Czech children. Diabetes Research and Clinical Practice,2003,60:49-56.
[18]Lars Hansen, Jan N. Jensen, Sandra Urioste, et al:No Associations to Late-Onset Type 2 Diabetes but an A45 Allele May Represent a Susceptibility Marker for Type 1 Diabetes Among Danes. DIABETES,2000,49:876:879.
[19]Iwata I,Nagafuchi S,Nakashima H,et al. Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the Japanese. Diabetes,1999,48: 416-419.
[20]Dupont S,Vionnet N,Chevre JC,et al. No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD 1 and PAX4 in Type Ⅱ diabetes in France. Diabetologia,1999,42(4):480-484.
[21]MockizukiM, Amemiya S, Kobayashi K, et al.() The association of Ala45Thr polymorphism in NeuroD with child onset diabetes in Japanese.Diabetes Res Clin 2002,Pract 55:11-17.
[22]Malecki MT, Klupa T, Moczulski DK, et al. The Ala45thr polymorphism of BETA2/NeuroDl gene and susceptibility to type 1 diabetes mellitus in Caucasians. Exp Clin Endocrinol Diab,2003,111:251-254.
[23]Kavvoura F.K,.John Ioannidis P.A. Ala45Thr polymorphism of the NEUROD1 gene and diabetes susceptibility:a meta-analysis. Hum Genet,2005,116:192-199.
[24]Limei Liu, Weiping Jia, Taishan Zheng, et al. Ala45Thr variation in neuroD1 gene is associated with early-onset type 2 diabetes with or without diabetic pedigree in Chinese. Mol Cell Biochem,2006,290:199-204.
[25]Ye I, Xu Y, Zhu Y, et al. Association of polymorphism in neurogenic differentiation factor 1 gene with type 2 diabetes. Zhongua Yi Xue Yi Chuan Xue Za Zhi,2002,19:484-487.
[26]叶林秀,徐焱成,朱宜莲,等.1型糖尿病病人神经源分化因子NeuroD/BETA2基因多态性研究.中国糖尿病杂志,2003,11(3)：216-217.
[27]Iwata I,Nagafuchi S,Nakashima H,et al. Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the Japanese. Diabetes,1999,48: 416-419.
[28]Azuma Kanatsuka, Yoshiharu Tokuyama, Osamu Nozaki,et al.β Cell Dysfunction in Late-Onset Diabetic Subjects Carrying Homozygous Mutation in Transcription Factors NeuroD1 and Pax4. Metabolism,2002,51:1161-1165.
[29]Smith SB,Watada H,Scheel DW,et al. Autoregulation and maturity onset diabetes of the young transcription factots control the human PAX4 promoter[J]. J Biol Chem,2000,275(47):36910-36919.
[30]Brink C,Chowdhury K,Gruss P. Pax4 regulatory elements mediate beta cell specific expression in the pancreas. Mech Dev,2001,100 (1):37-43.
[31]唐迅,李娜,胡永华.应用多因子降维法分析基因-基因交互作用.中华流行病学杂志,2006,27(5)：437-441
[1]Kitabchi AE. Ketosis-prone diabetes:a new subgroup of patients with atypical type 1 and type 2 diabetes? J Clin Endocrinol Metab,2003,88:5087-5089.
[2]Mauvais-Jarvis F,Sobngwi E,Porcher R,et al.Ketosis-prone type 2 diabetes in patients of Sub-Saharan African origin:clinical pathophysiology and natural history of beta-cell dysfunction and insulin resistance. Diabetes,2004,53: 645-653.
[3]Mauvais-Jarvis F,Smith SB,May CL,et al.PAX4 gene variations predispose to ketosis-prone diabetes. Human Molecular Genetics,2004,13:3151-3159.
[4]Jonsson J, Carlsson L, Edlund T,et al. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature,1994,371:606-609.
[5]Offield MF, Jetton TL, Labosky PA,et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development,1996; 122:983-995.
[6]Harrison KA, Thaler J, Pfaff SL, et al. Pancreas dorsal lobe agenesis and abnormal islets of Langerhans in Hlxb9-deficient mice. Nat Genet,1999; 23:71-5.
[7]Li H, Arber S, Jessell TM,et al. Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9. Nat Genet,1999,23:67-70.
[8]M Sander, L Sussel, J Conners, et al. Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development,2000,127:5533-5540.
[9]Sussel, L, Kalamaras J, Hartigan-O'Connor DJ, et al. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development.1998,125:2213-2221.
[10]Ahlgren U, Pfaff SL, Jessell TM,et al. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells.Nature,1997,385:257-60.
[11]St-Onge L, Sosa-Pineda B, Chowdhury K,et al. Pax6 is required for differentiation of glucagon-producing-cells in mouse pancreas. Nature,1997, 387:406-409
[12]Sander M, Neubuser A, Kalamaras J,et al. Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. Genes Dev,1997,11:16621-673
[13]Sosa-Pineda B, Chowdhury K, Torres M,et al. The Pax4 gene is essential for differentiation of insulin-producing b cells in the mammalian pancreas. Nature, 1997,386:399-402.
[14]Naya,F.J. Huang H P,Qiu Y et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes & Dev.1997,11:2323-2334
[15]Huang, H.P. Chu K,Eric N G,et al. Neogenesis of beta-cells in adult BETA2/NeuroD-deficien mice. Mol. Endocrinol.2002,16:541-551.
[16]Gradwohl G.,Dierich A, LeMeur M,et al.. Neurogenin3 is required for the development of the endocrine cell lineages of the pancreas. Proc. Natl. Acad. Sci. USA,2000,97:1607-1611.
[17]Gu G., Brown J.R., Melton D.A. Direct lineage tracing reveals the ontoge of pancreatic cell fates during mouse embryogenesis. Mech. Dev.2003,120: 35-43.
[18]Lee Y.H., Sauer B., Gonzalez F.J.. Laron dwarfism and non-insulin-dependent diabetes mellitus in the Hnf-lalpha knockout mouse. Mol. Cell Biol.1998,18: 3059-3068.
[19]Pontoglio M, Barra J, Hadchouel M,. et al. Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice. J. Clin. Invest.1998,101: 2215-2222.
[20]Kaestner K.H., The hepatocyte nuclear factor 3 (HNF3 or FOXA) family inmetabolism. Trends Endocrinol. Metab.2000,11:281-285.
[21]Swarup K. Chakrabartil and Raghavendra G. Mirmira.Transcription factors direct the development and function of pancreatic β cells. Trends Endocrinol. Metab.2003,14:78-85.
[22]Pilz, A. J., Povey, S., Gruss, P.; et al. Mapping of the human homologs of the murine paired-box-containing genes. Mammalian Genome,1993,4:78-82.
[23]Tamura. T., Izumikawa. Y., Kishino. T., et al. Assignment of the human PAX4 gene to chromosome band 7q32 by fluorescence in situ hybridization. Cytogenet Cell Genet.,1994,66:132-134.
[24]Sosa-Pineda B,Chowdhury K,Torres M,et al. The Pax4 gene is essential for diferentiation of insulin-producing beta cells in the mammalian pancreas Nature, 1997,386:399-402.
[25]J.M.Servitja, J.Ferrer, Transcriptional networks controlling pancreatic development and beta cell function.Diabetologia,2004,47:597-613.
[26]Smith S, Ee H, Conners J,et al. Paired-homeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development. Molecular and Cellular Biology,1999,19:8272-8280.
[27]Smith SB, Watada H, Scheel DW, et al. Autoregulation and maturity onset diabetes of the young transcription factors control the human PAX4 promoter. Journal of Biological Chemistry,2000,275:36910-36919.
[28]Sosa-Pineda B, Chowdhury K, Torres M, et al. The Pax4 gene is essential for differentiation of insulin-producing P cells in the mammalian pancreas. Nature,1997,386:399-402.
[29]Zhang YQ, Mashima H & Kojima I. Changes in the expression of transcription factors in pancreatic AR42J cells during differentiation into insulin-producing cells. Diabetes,2001,50:S10-S14.
[30]Heremans Y, Van De Casteele M, in't Veld P,et al. Recapitulation of embryonic neuroendocrine differentiation in adult human pancreatic duct cells expressing neurogenin 3. Journal of Cell Biology,2002,159:303-312.
[31]Kojima H, Fujimiya M, Matsumura K, et al. NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nature Medicine,2003,9:596-603.
[32]Theis M, Mas C, Doring B, et al. Replacement by a lacZ reporter gene assigns mouse connexin 36,45 and 43 to distinct cell types in pancreatic islets. Experimental Cell Research 2004,294:18-29.
[33]St-Onge L, Sosa-Pineda B, Chowdhury K, et al. Pax6 is required for differentiation of glucagon-producing a-cells in mouse pancreas. Nature. Smith SB,Watada H,Scheel DW,et al. Autoregulation and maturity onset diabetes of the young transcription factots control the human PAX4 promoter. J Biol Chem,2000,275:36910-36919.
[34]Brink C,Chowdhury K,Gruss P. Pax4 regulatory elements mediate beta cell specific expression in the pancreas. Mech Dev,2001,100:37-43.
[35]Kemp DM,Lin JC,Habener JF. Regulation of Pax4 paired homeodomain gene by neuron-restrictive silencer factor. J Biol Chem.2003;278:35057-62
[36]Fujitani Y,Kajimoto Y,Yasuda T,et al. Identification of a portable repression domain and an E1A-responsive activation domain in Pax4:a possible role of Pax4 as a transcriptional repressor in the pancreas. Mol. Cell. Biol.,1999, 19:8281-8291.
[37]Campbell SC,Cragg H, Elrick LJ et al.Inhibitory effect of pax4 on the human insulin and isleta myloid polypeptide(IAPP) promoters. FEBS Lett,1999,10: 53-57.
[38]Holm P, Rydlander B, Luthman H, et al. Interaction and association analysis of a type 1 diabetes susceptibility locus on chromosome 5q11-q13 and the 7q32 chromosomal region in Scandinavian families. Diabetes,2004,53:15842-15911.
[39]Blyszczuk P,Czyz J,Kania G,et al. Expression of Pax4 in embryonic stem cells promotes diferentiation of nestin-positive progenitor and insulin-producing cells. Proc Natl Acad Sci USA,2003,100 (3):998-1003.
[40]Biason-Lauber A, Boehm B, Lang-Muritano M, et al. Association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity. Diabetologia,2005,48(5):900-905.
[41]Hermann R, Mantere J, Lipponen K,et al. Lack of Association of PAX4 Gene With Type 1 Diabetes in the Finnish and Hungarian Populations. Diabetes 2005,54:2816-2819.
[42]Geng D. G., Liu S. Y., Steck A.et al.Comment on:Biason-Lauber A, Boehm B, Lang-Muritano M, et al (2005) Association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerativecapacity. Diabetologia 48:900-905. Diabetologia,2006,49:215-216
[43]Gylvin T, Bergholdt R, Nerup J, et al. To:Biason-Lauber A, Boehm B, Lang-Muritano M et al. association of childhood type 1 diabetes mellitus with a variant of PAX4:possible link to beta cell regenerative capacity.Diabetologia, 2005,48 (10):2183-2184
[44]张云,肖新华,王姮,等.PAX4基因A1168C多态性与中国汉族人1型糖尿病的相关性.中国医学科学院学报,2007,29(3)：370-373.
[45]Shimajiri Y, Sanke T, Furuta H, et al. A missense mutation of Pax4 gene (R121W) is associated with type 2 diabetes in Japanese.. Diabetes,2001,50: 2864-2869.
[46]Shimajiri Y,Shimabukuro M,Tomoyose T,et al. PAX4 mutation(R121W)as a prodiabetic variant in Okinawans. Biochem Biophys Res Commun,2003,302 (2): 342-344.
[47]Dupont S,Vionnet N,Chevre JC,et al. No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in Type Ⅱ diabetes in France. Diabetologia,1999,42(4):480-484.
[48]Tao T, Wasson J, Bemal-Mizrachi E, et al. Isolation and characterization of the human PAX4 gene.Diabetes,1998,47:1650-1653
[49]Mauvais-Jarvis F,Smith SB,Le May C,et al. PAX4 gene variations predispose to ketosis-prone diabetes. Hum Mol Genet,2004,13 (24):3151-3159.
[50]Apelqvist A, Li H, Sommer L, et al. Notch signalling controls pancreatic cell differentiation. Nature,1999,400:877-881.
[51]Jensen J, Pedersen EE, Galante P, et al. control of endodermal development by Hes-1. Nat Genet,2000,24:36-44.
[52]Naya FJ,Huang HP,Qin Y,et al. Diabetes defective pancreatic morphogenesis, and abnormal enteroendocirine differentiation in BETA2/neuroD-deficient mice[J]Genes Dev 1997,11(18):2323-2334.
[53]Malecki MT,Jhala US,Antonellis A,et al. Mutation in Neurod 1 are associated with the development of type 2 diabetes meilitus. Nature Genetics,1999,23: 323-328.
[54]Kristinsson SY,Thorolfsdottir ET,Talseth B,et at. MODY in Iceland is associated with mutations in HNF-1a and a novel mutation in NeuroD1. Diabetologia,2001, 44:2098-2103.
[55]Limei Liu, Weiping Jia, Taishan Zheng, et al. Ala45Thr variation in neuroD1 gene is associatedwith early-onset type 2 diabetes with or without diabetic pedigree in Chinese. Molecular and Cellular Biochemistry,2006,290:199-204.
[56]Kanatsuka A,Tokuyama Y,Nozaki O,et al.Beta-cell dysfunction in subjects carrying homozygous mutation in transcription factors Neurod1 and Pax4. Metabolism,2002,51:1161-1165.
[57]Copeman JB,Cucca F,Hearne CM,et al. Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene(IDDM7) to chromosome 2q31-q33. Nat Genet,1995,9:80-85.
[58]Iwata I,Nagafuchi S,Nakashima H,et al. Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the Japanese. Diabetes,1999,48: 416-419.
[59]Lars Hansen, Jan N. Jensen, Sandra Urioste, et al:No Associations to Late-Onset Type 2 Diabetes but an A45 Allele May Represent a Susceptibility Marker for Type 1 Diabetes Among Danes. DIABETES,2000,49:876-879.
[60]Malecki MT,Cyganek K,Klupa T,et al. The Ala45Thr polymorphism of BETA2 /NeuroDl gene and susceptibility to type 2 diabetes mellitus in a Polish population. Acta Diabetol,2003,40:109-111.
[61]Mochizuki M,Amemiya S,Kobayashi K,et al. The association of Ala45Thr polymorphism in NeuroD with child-onset Type 1a diabetes in Japanese. Diabetes Res Clin Pract,2002,55:11-17.
[62]Satoru Yamada,Yoshko Motohashi,Tatsuo Yanagawa, et al. NeuroD/BETA2 Gene G→A Polymorphism May Affect Onset Pattern of Type 1 Diabetes in Japanese. Diabetes Care,2001,24:1438-1441.
[63]Ondrej Cinek, Pavel Drevmek,Zdenek Summk, et al:NEUROD polymorphism Ala45Thr is associated with Type 1 diabetes mellitus in Czech children. Diabetes Research and Clinical Practice,2003,60:49-56.
[64]S.Dupont,N.Vionnet, J.C.Ch.vre, et al:No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in Type II diabetes in France. Diabetologia,1999,42:480-484.
[65]Takuya Awata,Kiyoaki Inoue,Ikuo Inoue,et al:Lack of association of the Ala45Thr variant in theBETA2:NEUROD1 with type 1 diabetes in Japanese. Diabetes Research and Clinical Practice,2000,49:61-63.
[66]韩学尧,刘春雁,纪立农.MODY6基因在家族性2型糖尿病发病中的作用中华医学杂志,2005,85(35)：2463-2467.
[67]叶林秀,徐焱成,朱宜莲,等.1型糖尿病病人神经源分化因子NeuroD/BETA2基因多态性研究.中国糖尿病杂志,2003,11(3)：216-217.
[68]Baumhueter S, Mendel DB, Conley PB,et al:HNF-1 shares three sequence motifs with the POU domain proteins and is identical to LF-B1 and APF. Genes Dev,1990,4:372-379.
[69]Bach, I., Galcheva-Gargova, Z., Mattei, M.-G.,et al. Cloning of human hepatic nuclear factor 1 (HNF1) and chromosomal localization of its gene in man and mouse. Genomics,1990,8:155-164.
[70]Yamagata K, Oda N, Kaisaki PJ,et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature, 1996,384:455-458.
[71]Winter WE,Nakamura M,House DV. Monogenic diabetes mellitus in youth.The MODY syndromes. Endocrinol Metab Clin North AM,1999,28:765-785.
[72]Yanuka Kashles O,Cohen H,Cihail T,et al. Transcriptional regulation of the Phosphoenolpyruvate carboxykinase gene by cooperation between hepatic nuclear factors. Mol Cell Biol,1994,14:7124-7133.
[73]Menzel R,Kaisaki PJ,Rjasanowski I,et al. A low renal threshold for glucose in diabetic patients with a mutation in the hepatocyte nuclear factor-1 alpha(HNF-lalpha) gene. Diabet Med,1998,15:816-820.
[74]Pontoglio M, Barra J, Hadchouel M, et al. Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell,1996,84(4):575-85.
[75]Pontoglio M, Sreenan S, Roe M, et al. Defective insulin secretion in hepatocyte nuclear factor 1 alpha-deficient mice. J Clin Invest,1998,101:2215-2222.
[76]Boj SF, Parrizas M, Maestro MA,et al. A transcription factor regulatory circuit in differentiated pancreatic cells. Proc Natl Acad Sci USA,2001,98: 14481-14486.
[77]Shih DQ, Screenan S, Munoz KN et al. Loss of HNF-lalpha function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism. Diabetes,2001,50:2472-2480.
[78]Farrelly AM, Wobser H, Bonner C,et al. Early loss of mammalian target of rapamycin complex 1 (mTORC1) signalling and reduction in cell size during dominant-negative suppression of hepatic nuclear factor 1-alpha(HNF1A) function in INS-1 insulinoma cell. Diabetologia.2009,52(1):136-44.
[79]Finegood, D. T., Scaglia, L.,et al. Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes,1995,44: 249-256.
[80]Ferrer J. A genetic switch in pancreatic beta-cells:implications for differentiation and haploinsufficiency. Diabetes,2002,51:2355-2362.
[81]Stoffel M, Duncan SA. The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci USA,1997,94: 13209-13214.
[82]Vaxillaire M, Abderrahmani A, Boutin P et al. Anatomy of a homeoprotein revealed by the analysis of human MODY3 mutations. J Biol Chem,1999,274: 35639-35646.
[83]Hansen SK, Parrizas M, Jensen ML et al. Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function. J Clin Invest,2000,110:827-833.
[84]Thomas H, Badenberg B, Bulman M et al. Evidence for haploinsufficiency of the human HNF1alpha gene revealed by functional characterization of MODY3-associated mutations. Biol Chem,1998,383:1691-1700.
[85]Gragnoli C, Lindner T, Cockburn BN et al. Maturity-onset diabetes of the young due to a mutation in the hepatocyte nuclear factor-4 alpha binding site in the promoter of the hepatocyte nuclear factor-1 alpha gene.Diabetes,1997,46: 1648-1651.
[86]Moller AM,Dalgaard LT,Pociot F,et al. Mutation in the hepatocyte nuclear factor-1 alpha gene in Caucasian families originally classified as having Typel diabetes. Diabetologia,1998,41:1528-1531.
[87]Yamada, S., Nishigori, H., Onda, H.,et al. Identification of mutations in the hepatocyte nuclear factor (HNF)-1-alpha gene in Japanese subjects with IDDM. Diabetes,1997,46:1643-1647.
[88]Yoshiuchi, I., Yamagata, K.;,Yoshimoto, M.,et al. Analysis of a non-functional HNF-1-alpha (TCF1) mutation in Japanese subjects with familial type 1 diabetes. Hum. Mutat.2001,18:345-351.
[89]Yoshiuchi, I., Yamagata, K.,Yang Q,et al. Three new mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with diabetes mellitus:clinical features and functional characterization. Diabetologia,1999,42:621-626.
[90]Kawasaki E,Sera Y,Yamakawa K,et al. Identification and functional analysis of mutation in the hepatocyte nuclear factor-1alpha gene in anti-islet autoantibody-negativeJapanese patients with type 1 diabetes. J Clin Endocrinal Metab,2000,85:331-335.
[91]Byrne M. M.,Sturis J.,Menzel S.,et al. Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Diabetes,1996,45: 1503-1510.
[92]Yamagata K., Oda N., Kalsaki P. J.,et al. Mutations in the hepatocyte nuclear factor-1-alpha gene in maturity-onset diabetes of the young (MODY3). Nature, 1996,384:455-457.
[93]Kaisaki P. J., Menzel S., Lindner T.,et al. Mutations in the hepatocyte nuclear factor-1-alpha gene in MODY and early-onset NIDDM:evidence for a mutational hotspot in exon 4. Diabetes,1997,46:528-535.
[94]韩学尧,纪立农.MODY3基因在早发家族性2型糖尿病发病中的作用.中国糖尿病杂志,2007,15(3)：153-155.
[95]方启晨,张蓉,王从容,等.中国人早发及多发糖尿病家系HNF-1α基因突变的筛查.中华医学遗传学杂志,2004,21(4)：329-334.
[96]Chiu K.C.,Chuang L.M., Ryu J. M.,et al. The I27L amino acid polymorphism of hepatic nuclear factor-1-alpha is associated with insulin resistance. J. Clin. Endocr. Metab.,2000,85:2178-2183.
[97]Babaya, N.; Ikegami, H.; Fujisawa, T.;et al. Association of I27L polymorphism of hepatocyte nuclear factor-1-alpha gene with high-density lipoprotein cholesterol level. J. Clin. Endocr. Metab.,2003,88:2548-2551.
[98]Hegele, R. A.; Cao, H.; Harris, S. B.;et al. The hepatic nuclear factor-1-alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. J. Clin. Endocr. Metab,1999,84:1077-1082.
[99]Triggs-Raine, B. L.; Kirkpatrick, R. D.; Kelly, S. L.;et al. HNF1-alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community. Proc. Nat. Acad.Sci.,2002,99:4614-4619.
[100]马立隽,卞茸文,王华,等.中国人MODY/NIDDM家系葡萄糖激酶和肝细胞核因子1α基因缺陷的分子筛查.中华内分泌代谢杂志,2003,19(3)：216-220.