中国人群2型糖尿病易感基因CDC2L2的筛选及其参与胰岛β细胞凋亡途径的研究
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摘要
背景与目的:2型糖尿病(Type 2 Diabetes,T2D)是一种具有明显遗传倾向的复杂多基因疾病。本实验室全基因组扫描结果显示,1号染色体上有3个区域(1p36.23-36.33、1q24.3-25.1及1q42.12-42.13)与2型糖尿病相连锁。本项研究主要目的是利用单核苷酸多态性(SNP)标记在各定位区域内寻找2型糖尿病的易感基因。并对它们可能的作用途径进行初步探讨。
方法:用测序法对上述区域中4个候选基因(sAC、PANK4、CASPASE9和CDC2L2)SNP位点在467例北方汉族2型糖尿病患者和569例对照个体进行基因分型及病例-对照关联分析,并对同一基因内具有显著性关联的SNP位点进行单倍型分析。在76个2型糖尿病家系中进行基因分型,并进行TDT/sibTDT研究来对病例一对照分析结果进行验证。为了检验人群分层对关联分析的影响,各个SNP位点分别对年龄、性别和身体质量指数(BMI)等参数进行分层分析。
将筛选到的2型糖尿病易感基因CDC2L2克隆到pcDNA3.1表达载体,转染胰岛β细胞(INS-1),用Western Blotting方法检测与细胞生长和凋亡相关的信号通路中关键蛋白表达水平和磷酸化水平的改变情况,确定其以何种途径参与对细胞生存能力和增殖的调节。
结果:sAC基因中rs203849和rs203826、PANK4基因中rs7535528和CASPASE9基因中rs884363位点的基因频率在病例与对照组中分布没有显著性差异。CDC2L2基因中6个SNP位点基因频率在病例组与对照组中分布存在显著差异(SNP11:P=0.018,OR(95%CI)=0.78(0.64-0.96):rs1059831:P=0.043,OR(95%CI)=0.81(0.66-0.99);SNP33:P=0.028,OR(95%CI)=0.79(0.65-0.98);SNP36:P=0.040,OR(95%CI)=0.81(0.66-0.99);rs11488590:P=0.035,OR(95%CI)=0.80(0.66-0.98)和SNP30:P=0.029,OR(95%CI)=0.80(0.66-0.98))。CDC2L2基因中这6个SNP位点之间存在着显著的连锁不平衡(r~2＞0.5,D'＞0.85,p＜0.001)。在这6个SNP位点组成的单倍型中,有两种在病例和对照组中的分布频率有显著差异:T-A-G-G-C-A(P=0.041,OR(95%CI) =1.22(1.01-1.47)),C--A-A-T-G(P=0.015,OR(95%CI)=0.77(0.63-0.95))。在显型模式分析中,CDC2L2基因中5个位点的基因型在病例和对照组分布差异呈显著性(rs1059831:P=0.026;SNP33:P=0.0097;rs9793240:P=0.025;SNP36:P=0.042;rs11488590:P=0.026)。虽然SNP11位点在于DT分析中没有达到显著性,但仍然验证了病例对照研究的正确性。另外,分层分析显示:在老年(Age＞44)、女性和非肥胖(BMI＜23)人群中,CDC2L2基因中SNP11与2型糖尿病有显著关联关系(P值分别为:0.011、0.018和0.009);而在成年(Age≤44)、男性和肥胖(BMI＞23)人群中则无关联性(P值分别为:0.644、0.498和0.322)。PANK4基因中rs7535528位点在女性和非肥胖人群中也与2型糖尿病呈显著关联关系(P值分别为:0.033和0.020)。Logistic回归显示PANK4和CDC2L2基因之间存在交互作用。
CDC2L2基因产物p58PITSLRE和其被Caspase3切割产物(p110C)参与细胞凋亡过程。p58和p110C基因转染胰岛β细胞(INS-1)后都能显著抑制FAK活性,但两者作用途径不同:p58是通过降低FAK397位Tyr的磷酸化,而p110C则是降低细胞中总FAK水平。
结论:以上结果表明在1号染色体1p36.33区域中CDC2L2基因是一个2型糖尿病易感基因。其表达产物p58 P17SLRE和C端多肽(p110C)参与对FAK活性的调节,促进胰岛β细胞(mNS-1)凋亡。
Background and Objective Type 2 diabetes is a complex disorder with a strong genetic background.Our previous genome-wide scanning suggested that 3 regions in chromosomes 1 showed evidence of linkage with type 2 diabetes.Aim of this paper is to search for the susceptibility variant(s) of type 2 diabetes in these three susceptible regions by genotyping SNP markers in case-control DNA samples.Another purpose of this study is to gain insight into the function of these genes.
Methods SNPs from 4 candidate genes(sAC,PANK4,CASPASE9 and CDC2L2) in the mapped regions were chosen from public SNP data or identified by sequencing the samples.These loci are further evaluated in Han Chinese individuals comprising of 467 patients and 569 normal subjects and 76 parent-offspring trios by TDT analysis.The haplotypes within a gene are further analyzed.
We construct of expression vector of p58 PITSLRE and p110C and transfect beta-cell(INS-1).Using of western blotting to measure the expression and phosphorylation levels of the key molecules in the pathway relating to cell survival and apoptosis.
Results SNPs of PANK4,CASPASE9 and sAC genes didn't show significant association with diabetes status.Six SNPs of CDC2L2 gene were shown to be significantly associated with T2D:rs1059831:P = 0.043,OR = 0.81(CI 95% 0.66-0.99);SNP33:P= 0.028,OR = 0.79(CI 95%0.65-0.98);SNP11:P= 0.018, OR = 0.78(CI 95%0.64-0.96);SNP36:P= 0.040,OR = 0.81(CI 95%0.66-0.99); rs11488590:P= 0.035,OR = 0.80(CI 95%0.66-0.98) and SNP30:P= 0.029,OR = 0.80(CI 95%0.66-0.98).The pairs of these six SNPs in CDC2L2 gene showed strong LD(r~2＞0.5,P＜0.001).Two haplotypes in CDC2L2 were observed to be associated with T2D(T-A-G-G-C-A:P=0.041,OR=1.22(CI 95%1.01-1.47) and C- -A-A-T-G:P=0.015,OR=0.77(CI 95%0.63 - 0.95)).The data informatively showed that offspring carrying the protective alleles in these six variations had a lower risk for T2D under dominant model(rs1059831:P=0.026;SNP33: P=0.0097;SNP11:P=0.025;SNP36:P=0.042;rs11488590:P=0.026).When individuals were stratified by age,sex and Body Mass Index,the SNP11 of CDC2L2 gene was strongly associated with T2D female patients,those who were over 44 years old,whose BMI was less than 23(P = 0.018,0.011 and 0.0089, respectively).However,it was not replicated in family-based TDT analysis(P = 0.085,OR = 0.63(CI 95%0.34 - 1.06)).In spite of this,the TDT results also clearly indicated that minor-allele for SNP11 was a protective allele for T2D, supporting the result performed in case-control study.In addition,rs7535528 of PANK4 is strongly associated with T2D female patients and those who BMI was less than 23(P = 0.033 and 0.020,respectively).The data showed that the synergetic effect of PANK4 and CDC2L2 is responsible for the development of type 2 diabetes.
Overexpression of p58 and p110C in INS-1 cell both can decrease the activity of FAK,but the means of them were different:p58 was by decreasing phosphorylation level of FAK(Tyr 397) and p110C was by decreasing the level of FAK expression.
Conclusion Our data confer that the CDC2L2 gene may contribute to the susceptibility of type 2 diabetes in Northern Han Chinese population.P58 PITSLRE and p110C might be involved in apoptosis by regulating the intergrin-FAK pathway.
方法:用测序法对上述区域中4个候选基因(sAC、PANK4、CASPASE9和CDC2L2)SNP位点在467例北方汉族2型糖尿病患者和569例对照个体进行基因分型及病例-对照关联分析,并对同一基因内具有显著性关联的SNP位点进行单倍型分析。在76个2型糖尿病家系中进行基因分型,并进行TDT/sibTDT研究来对病例一对照分析结果进行验证。为了检验人群分层对关联分析的影响,各个SNP位点分别对年龄、性别和身体质量指数(BMI)等参数进行分层分析。
将筛选到的2型糖尿病易感基因CDC2L2克隆到pcDNA3.1表达载体,转染胰岛β细胞(INS-1),用Western Blotting方法检测与细胞生长和凋亡相关的信号通路中关键蛋白表达水平和磷酸化水平的改变情况,确定其以何种途径参与对细胞生存能力和增殖的调节。
结果:sAC基因中rs203849和rs203826、PANK4基因中rs7535528和CASPASE9基因中rs884363位点的基因频率在病例与对照组中分布没有显著性差异。CDC2L2基因中6个SNP位点基因频率在病例组与对照组中分布存在显著差异(SNP11:P=0.018,OR(95%CI)=0.78(0.64-0.96):rs1059831:P=0.043,OR(95%CI)=0.81(0.66-0.99);SNP33:P=0.028,OR(95%CI)=0.79(0.65-0.98);SNP36:P=0.040,OR(95%CI)=0.81(0.66-0.99);rs11488590:P=0.035,OR(95%CI)=0.80(0.66-0.98)和SNP30:P=0.029,OR(95%CI)=0.80(0.66-0.98))。CDC2L2基因中这6个SNP位点之间存在着显著的连锁不平衡(r~2＞0.5,D'＞0.85,p＜0.001)。在这6个SNP位点组成的单倍型中,有两种在病例和对照组中的分布频率有显著差异:T-A-G-G-C-A(P=0.041,OR(95%CI) =1.22(1.01-1.47)),C--A-A-T-G(P=0.015,OR(95%CI)=0.77(0.63-0.95))。在显型模式分析中,CDC2L2基因中5个位点的基因型在病例和对照组分布差异呈显著性(rs1059831:P=0.026;SNP33:P=0.0097;rs9793240:P=0.025;SNP36:P=0.042;rs11488590:P=0.026)。虽然SNP11位点在于DT分析中没有达到显著性,但仍然验证了病例对照研究的正确性。另外,分层分析显示:在老年(Age＞44)、女性和非肥胖(BMI＜23)人群中,CDC2L2基因中SNP11与2型糖尿病有显著关联关系(P值分别为:0.011、0.018和0.009);而在成年(Age≤44)、男性和肥胖(BMI＞23)人群中则无关联性(P值分别为:0.644、0.498和0.322)。PANK4基因中rs7535528位点在女性和非肥胖人群中也与2型糖尿病呈显著关联关系(P值分别为:0.033和0.020)。Logistic回归显示PANK4和CDC2L2基因之间存在交互作用。
CDC2L2基因产物p58PITSLRE和其被Caspase3切割产物(p110C)参与细胞凋亡过程。p58和p110C基因转染胰岛β细胞(INS-1)后都能显著抑制FAK活性,但两者作用途径不同:p58是通过降低FAK397位Tyr的磷酸化,而p110C则是降低细胞中总FAK水平。
结论:以上结果表明在1号染色体1p36.33区域中CDC2L2基因是一个2型糖尿病易感基因。其表达产物p58 P17SLRE和C端多肽(p110C)参与对FAK活性的调节,促进胰岛β细胞(mNS-1)凋亡。
Background and Objective Type 2 diabetes is a complex disorder with a strong genetic background.Our previous genome-wide scanning suggested that 3 regions in chromosomes 1 showed evidence of linkage with type 2 diabetes.Aim of this paper is to search for the susceptibility variant(s) of type 2 diabetes in these three susceptible regions by genotyping SNP markers in case-control DNA samples.Another purpose of this study is to gain insight into the function of these genes.
Methods SNPs from 4 candidate genes(sAC,PANK4,CASPASE9 and CDC2L2) in the mapped regions were chosen from public SNP data or identified by sequencing the samples.These loci are further evaluated in Han Chinese individuals comprising of 467 patients and 569 normal subjects and 76 parent-offspring trios by TDT analysis.The haplotypes within a gene are further analyzed.
We construct of expression vector of p58 PITSLRE and p110C and transfect beta-cell(INS-1).Using of western blotting to measure the expression and phosphorylation levels of the key molecules in the pathway relating to cell survival and apoptosis.
Results SNPs of PANK4,CASPASE9 and sAC genes didn't show significant association with diabetes status.Six SNPs of CDC2L2 gene were shown to be significantly associated with T2D:rs1059831:P = 0.043,OR = 0.81(CI 95% 0.66-0.99);SNP33:P= 0.028,OR = 0.79(CI 95%0.65-0.98);SNP11:P= 0.018, OR = 0.78(CI 95%0.64-0.96);SNP36:P= 0.040,OR = 0.81(CI 95%0.66-0.99); rs11488590:P= 0.035,OR = 0.80(CI 95%0.66-0.98) and SNP30:P= 0.029,OR = 0.80(CI 95%0.66-0.98).The pairs of these six SNPs in CDC2L2 gene showed strong LD(r~2＞0.5,P＜0.001).Two haplotypes in CDC2L2 were observed to be associated with T2D(T-A-G-G-C-A:P=0.041,OR=1.22(CI 95%1.01-1.47) and C- -A-A-T-G:P=0.015,OR=0.77(CI 95%0.63 - 0.95)).The data informatively showed that offspring carrying the protective alleles in these six variations had a lower risk for T2D under dominant model(rs1059831:P=0.026;SNP33: P=0.0097;SNP11:P=0.025;SNP36:P=0.042;rs11488590:P=0.026).When individuals were stratified by age,sex and Body Mass Index,the SNP11 of CDC2L2 gene was strongly associated with T2D female patients,those who were over 44 years old,whose BMI was less than 23(P = 0.018,0.011 and 0.0089, respectively).However,it was not replicated in family-based TDT analysis(P = 0.085,OR = 0.63(CI 95%0.34 - 1.06)).In spite of this,the TDT results also clearly indicated that minor-allele for SNP11 was a protective allele for T2D, supporting the result performed in case-control study.In addition,rs7535528 of PANK4 is strongly associated with T2D female patients and those who BMI was less than 23(P = 0.033 and 0.020,respectively).The data showed that the synergetic effect of PANK4 and CDC2L2 is responsible for the development of type 2 diabetes.
Overexpression of p58 and p110C in INS-1 cell both can decrease the activity of FAK,but the means of them were different:p58 was by decreasing phosphorylation level of FAK(Tyr 397) and p110C was by decreasing the level of FAK expression.
Conclusion Our data confer that the CDC2L2 gene may contribute to the susceptibility of type 2 diabetes in Northern Han Chinese population.P58 PITSLRE and p110C might be involved in apoptosis by regulating the intergrin-FAK pathway.
引文
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