中国人2型糖尿病易感基因的定位与鉴定
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摘要
2型糖尿病是多基因复杂病,且在不同人种中遗传异质性较大,本研究采用候选基因和定位克隆两种研究策略,对中国人2型糖尿病的易感基因进行鉴定和定位,同时评价公共数据库中国人SNP数据在上海地区汉族人的应用性。
1.中国人2型糖尿病的候选基因关联研究
使用候选基因法,研究了与糖脂代谢相关的转录因子过氧化物酶增殖激活受体(peroxisome proliferator activated receptor delta,PPARD)基因、与内质网应激相关的激活转录因子6(activating transcription factor 6,ATF6)基因和新发现的脂肪细胞因子视黄醇结合蛋白4(retinol binding protein 4,RBP4)基因多态性与中国人2型糖尿病的相关性。对于PPARD和ATF6基因,我们入选287名2型糖尿病患者和376名正常对照者,使用聚合酶链反应限制性片断长度多态性法检测SNP位点基因型,发现PPARD基因-87 T>C多态位点与中国人糖代谢相关,C等位基因携带者的空腹(对照组:4.85±0.04 vs 4.99±0.04,P=0.0078;病例组:6.89±0.12 vs 7.84±0.18,P<0.0001)及糖刺激后2小时血糖水平(病例组:13.53±0.23 vs 14.89±0.33,P<0.0001)显著高于T/T纯合子,且胰岛素抵抗状态显著(胰岛素敏感性指数,对照组:3.29±0.08 vs 3.06±0.07,P=0.0365;病例组:1.51±0.03 vs 1.42±0.03,P=0.0058)。ATF6基因多态位点Ala145Pro与中国人早发2型糖尿病相关,Ala等位基因频率在早发2型糖尿病家系先证者中频率显著高于正常对照人群(77.6% vs 69.4%,P=0.0417)。Ala145Pro与中国人脂代谢相关,Pro等位基因携带者高密度脂蛋白胆固醇水平较低(1.33±0.02 vs 1.25±0.02,P=0.0140)。对于RBP4基因,我们首先在32个样本中对基因外显子、1kb启动子和部分内含子进行测序寻找SNP位点,并进行连锁不平衡分析选取标签SNP,继而在255个2型糖尿病患者和372个正常对照人群检测了5个标签SNP,发现+5388 C>T、+8201 T>A和+8204 T>A组成的单体型CAA在2型糖尿病组中显著高于正常对照组(0.5% vs 1.8%,P=0.0343,经验P值为0.0659),且+5388 C>T与正常对照者中空腹及糖刺激后2小时C肽水平显著相关,T等位基因携带者水平较高(空腹C肽:1.80±0.05 vs 1.56±0.07,P=0.0162;2小时C肽:7.15±0.26 vs 5.71±0.38,P=0.0075)。此外,本研究还见到RBP4基因+5388 C>T等多态位点与血清RBP4水平相关。
2.国际单体型图谱计划数据在上海汉族人群中的应用性评价
国际单体型图谱计划,简称HapMap计划,提供了包括中国北方汉族人在内的四个人群全基因组400万个SNP位点的频率及各染色体区域LD和标签SNP的信息,是关联研究设计的重要工具,但其是否能有效代表中国南方汉族人的遗传信息尚未见报道。我们使用国际2型糖尿病染色体1q协作组数据对HapMap计划数据库在上海地区汉族人中进行应用性评价,发现HapMap计划中国人数据与上海地区汉族人在等位基因频率分布、相邻SNP间r2值和单体型频率高度一致(R值依次为0.94、0.97、0.99,P值均<0.0001),且HapMap数据中选取的标签SNP能有效代表上海地区汉族人的遗传信息,r2=0.8时,93.8%的SNP可被标记。因此,HapMap计划可为中国人群多基因疾病遗传关联研究的设计提供初步信息。
3.1q23.3区域中国人2型糖尿病易感基因的定位
前期研究中,我们发现在染色体1q21-q25区域存在连锁信号,国际2型糖尿病染色体1q协作组的精细作图研究进一步将其中之一定位于1q23.3区域中,在此基础上,我们对染色体1q23.3区域中国人2型糖尿病易感基因进行了定位研究。本研究从HapMap计划中国人数据库中挑选标签SNP,结合考虑SNP位点所在区域的功能,共选取94个SNP,使用时间飞行质谱技术在1892例2型糖尿病患者和1808例正常对照者中检测各SNP基因型。经过数据质控分析,共3491例样本、73个SNP的数据为有效数据。经单点SNP分析,本研究发现位于NOS1AP基因内含子2中的SNP位点rs12742393与2型糖尿病高度相关,C等位基因在2型糖尿病患者中显著升高(25.2% vs 21.6%,P=0.0004,经验P值为0.0342),由rs4531272 - rs12742393组成的单体型T-C在2型糖尿病组显著高于正常对照组(52.6% vs 49.5%,P=0.0092,经验P值为0.0424)。在正常人群中分析P值小于0.05的SNP位点发现位于NOS1AP基因的rs1415263与血清总胆固醇(TT vs TC vs CC:5.13±0.06 vs 4.99±0.03 vs 4.94±0.09,P < 0.05)和低密度脂蛋白胆固醇(TT vs TC vs CC:3.45±0.05 vs 3.36±0.03 vs 3.24±0.04,P < 0.05)水平相关;rs12029454与低密度脂蛋白胆固醇相关(GG vs GA vs AA:3.27±0.03 vs 3.39±0.03 vs 3.46±0.07,P < 0.05)。
Type 2 diabetes is a complex genetic disease with heterogeneity among populations. In this study, we used the strategy of candidate gene and positional cloning to identify susceptible genes of type 2 diabetes in the Chinese population. We also evaluated the transferability of HapMap Chinese data among Shanghai population.
1. Candidate gene association study on type 2 diabetes in Chinese
First, we analyzed the association between diabetes and three candidate genes, peroxisome proliferator activated receptor delta (PPARD), activating transcription factor 6 (ATF6) and retinol binding protein 4 (RBP4). A total of 287 diabetic patients and 376 normal controls were recruited and genotyped for the single nucleotide polymorphisms (SNPs)–87 T>C of PPARD as well as Ala145Pro of ATF6. We found C allele carriers of PPARD–87 T>C had significantly higher plasma glucose levels at both fasting status (controls: 4.85±0.04 vs 4.99±0.04, P = 0.0078; cases: 6.89±0.12 vs 7.84±0.18, P < 0.0001) and 2 hours after glucose stimulation (cases: 13.53±0.23 vs 14.89±0.33, P < 0.0001). Meanwhile, poorer insulin sensitivity (controls: 3.29±0.08 vs 3.06±0.07, P=0.0365; cases: 1.51±0.03 vs 1.42±0.03, P = 0.0058) was detected among them. The Ala allele of ATF6 Ala145Pro was significantly more frequent in the probands of early onset type 2 diabetic pedigrees (77.6% vs 69.4%, P = 0.0417). The Pro allele carriers had significantly lower high-density lipoprotein cholesterol levels (1.33±0.02 vs 1.25±0.02, P = 0.0140). For RBP4, we sequenced exons and the putative promoter region in 32 subjects to identify variants. Taking account of the pairwise linkage disequilibrium (LD) and minor allele frequencies, five SNPs were further genotyped in 255 type 2 diabetes patients and 372 normal controls. We found a rare haplotype CAA formed by +5388 C>T, +8201 T>A and +8204 T>A was more frequent in diabetic patients (P=0.0343, empirical P=0.0659). In the normal controls, the SNP +5388 C>T was associated with serum C-peptide levels at both fasting status (1.80±0.05 vs 1.56±0.07, P=0.0162) and 2-hours after glucose stimulation (7.15±0.26 vs 5.71±0.38, P=0.0075). The non-coding SNPs were also found to be associated with circulating RBP4 concentrations in both groups (P<0.05).
2. Evaluation the transferability of HapMap Chinese data in a Shanghai population
The HapMap project catalogs millions of common SNPs in the human genome in four major populations including northern Hans, with the aim to facilitate association studies on complex diseases. In this study, we used genotype data from International Type 2 Diabetes 1q Consortium to examine the transferability of HapMap Chinese data in Shanghai population. The HapMap Chinese data showed high consistence with Shanghai population on allele frequencies, LD coefficient r2 and haplotype frequencies (R=0.94, 0.97, 0.99 respectively, all P<0.0001). In addition, tagging SNP set selected from HapMap Chinese data also performed well in Shanghai population with the threshold 0.8 of r2 to cover 93.8% of the SNPs. The HapMap SNP data performed well in the Shanghai population and thus could be a powerful tool for the genetic studies on complex disease in southern Hans.
3. Positional cloning study of type 2 diabetes susceptible gene on chromosome 1q23.3 in Chinese
Previously, we detected a linkage signal of type 2 diabetes on chromosome 1q21-q25. International Type 2 Diabetes 1q Consortium then did a fine mapping analysis and located one of the susceptible genes on chromosome 1q23.3. In this study, we did a positional cloning study based on the previous linkage and fine mapping studies. Considering both LD and potential SNP function, 94 SNP were selected from HapMap data and genotyped in 1892 diabetic patients and 1808 normal controls using matrix-assisted laser desorption inoization-time of flight mass spectrometry. After quality control of genotyping, a total of 3491 individuals and 73 SNPs were analyzed. We found rs12742393, located in intron2 of NOS1AP, was associated with type 2 diabetes, C allele was significantly higher in the cases (25.2% vs 21.6%, P = 0.0004, empirical P = 0.0342). The haplotype TC formed by rs4531272 - rs12742393 was also significantly more frequent in the cases (52.6% vs 49.5%, P = 0.0092, empirical P = 0.0424). In the normal controls, rs1415263 was associated with serum levels of total cholesterol (TT vs TC vs CC: 5.13±0.06 vs 4.99±0.03 vs 4.94±0.09, P < 0.05) and low-density lipoprotein cholesterol (TT vs TC vs CC: 3.45±0.05 vs 3.36±0.03 vs 3.24±0.04, P < 0.05). We also found rs12029454 was associated with serum level of low-density lipoprotein cholesterol (GG vs GA vs AA: 3.27±0.03 vs 3.39±0.03 vs 3.46±0.07, P < 0.05).
1.中国人2型糖尿病的候选基因关联研究
使用候选基因法,研究了与糖脂代谢相关的转录因子过氧化物酶增殖激活受体(peroxisome proliferator activated receptor delta,PPARD)基因、与内质网应激相关的激活转录因子6(activating transcription factor 6,ATF6)基因和新发现的脂肪细胞因子视黄醇结合蛋白4(retinol binding protein 4,RBP4)基因多态性与中国人2型糖尿病的相关性。对于PPARD和ATF6基因,我们入选287名2型糖尿病患者和376名正常对照者,使用聚合酶链反应限制性片断长度多态性法检测SNP位点基因型,发现PPARD基因-87 T>C多态位点与中国人糖代谢相关,C等位基因携带者的空腹(对照组:4.85±0.04 vs 4.99±0.04,P=0.0078;病例组:6.89±0.12 vs 7.84±0.18,P<0.0001)及糖刺激后2小时血糖水平(病例组:13.53±0.23 vs 14.89±0.33,P<0.0001)显著高于T/T纯合子,且胰岛素抵抗状态显著(胰岛素敏感性指数,对照组:3.29±0.08 vs 3.06±0.07,P=0.0365;病例组:1.51±0.03 vs 1.42±0.03,P=0.0058)。ATF6基因多态位点Ala145Pro与中国人早发2型糖尿病相关,Ala等位基因频率在早发2型糖尿病家系先证者中频率显著高于正常对照人群(77.6% vs 69.4%,P=0.0417)。Ala145Pro与中国人脂代谢相关,Pro等位基因携带者高密度脂蛋白胆固醇水平较低(1.33±0.02 vs 1.25±0.02,P=0.0140)。对于RBP4基因,我们首先在32个样本中对基因外显子、1kb启动子和部分内含子进行测序寻找SNP位点,并进行连锁不平衡分析选取标签SNP,继而在255个2型糖尿病患者和372个正常对照人群检测了5个标签SNP,发现+5388 C>T、+8201 T>A和+8204 T>A组成的单体型CAA在2型糖尿病组中显著高于正常对照组(0.5% vs 1.8%,P=0.0343,经验P值为0.0659),且+5388 C>T与正常对照者中空腹及糖刺激后2小时C肽水平显著相关,T等位基因携带者水平较高(空腹C肽:1.80±0.05 vs 1.56±0.07,P=0.0162;2小时C肽:7.15±0.26 vs 5.71±0.38,P=0.0075)。此外,本研究还见到RBP4基因+5388 C>T等多态位点与血清RBP4水平相关。
2.国际单体型图谱计划数据在上海汉族人群中的应用性评价
国际单体型图谱计划,简称HapMap计划,提供了包括中国北方汉族人在内的四个人群全基因组400万个SNP位点的频率及各染色体区域LD和标签SNP的信息,是关联研究设计的重要工具,但其是否能有效代表中国南方汉族人的遗传信息尚未见报道。我们使用国际2型糖尿病染色体1q协作组数据对HapMap计划数据库在上海地区汉族人中进行应用性评价,发现HapMap计划中国人数据与上海地区汉族人在等位基因频率分布、相邻SNP间r2值和单体型频率高度一致(R值依次为0.94、0.97、0.99,P值均<0.0001),且HapMap数据中选取的标签SNP能有效代表上海地区汉族人的遗传信息,r2=0.8时,93.8%的SNP可被标记。因此,HapMap计划可为中国人群多基因疾病遗传关联研究的设计提供初步信息。
3.1q23.3区域中国人2型糖尿病易感基因的定位
前期研究中,我们发现在染色体1q21-q25区域存在连锁信号,国际2型糖尿病染色体1q协作组的精细作图研究进一步将其中之一定位于1q23.3区域中,在此基础上,我们对染色体1q23.3区域中国人2型糖尿病易感基因进行了定位研究。本研究从HapMap计划中国人数据库中挑选标签SNP,结合考虑SNP位点所在区域的功能,共选取94个SNP,使用时间飞行质谱技术在1892例2型糖尿病患者和1808例正常对照者中检测各SNP基因型。经过数据质控分析,共3491例样本、73个SNP的数据为有效数据。经单点SNP分析,本研究发现位于NOS1AP基因内含子2中的SNP位点rs12742393与2型糖尿病高度相关,C等位基因在2型糖尿病患者中显著升高(25.2% vs 21.6%,P=0.0004,经验P值为0.0342),由rs4531272 - rs12742393组成的单体型T-C在2型糖尿病组显著高于正常对照组(52.6% vs 49.5%,P=0.0092,经验P值为0.0424)。在正常人群中分析P值小于0.05的SNP位点发现位于NOS1AP基因的rs1415263与血清总胆固醇(TT vs TC vs CC:5.13±0.06 vs 4.99±0.03 vs 4.94±0.09,P < 0.05)和低密度脂蛋白胆固醇(TT vs TC vs CC:3.45±0.05 vs 3.36±0.03 vs 3.24±0.04,P < 0.05)水平相关;rs12029454与低密度脂蛋白胆固醇相关(GG vs GA vs AA:3.27±0.03 vs 3.39±0.03 vs 3.46±0.07,P < 0.05)。
Type 2 diabetes is a complex genetic disease with heterogeneity among populations. In this study, we used the strategy of candidate gene and positional cloning to identify susceptible genes of type 2 diabetes in the Chinese population. We also evaluated the transferability of HapMap Chinese data among Shanghai population.
1. Candidate gene association study on type 2 diabetes in Chinese
First, we analyzed the association between diabetes and three candidate genes, peroxisome proliferator activated receptor delta (PPARD), activating transcription factor 6 (ATF6) and retinol binding protein 4 (RBP4). A total of 287 diabetic patients and 376 normal controls were recruited and genotyped for the single nucleotide polymorphisms (SNPs)–87 T>C of PPARD as well as Ala145Pro of ATF6. We found C allele carriers of PPARD–87 T>C had significantly higher plasma glucose levels at both fasting status (controls: 4.85±0.04 vs 4.99±0.04, P = 0.0078; cases: 6.89±0.12 vs 7.84±0.18, P < 0.0001) and 2 hours after glucose stimulation (cases: 13.53±0.23 vs 14.89±0.33, P < 0.0001). Meanwhile, poorer insulin sensitivity (controls: 3.29±0.08 vs 3.06±0.07, P=0.0365; cases: 1.51±0.03 vs 1.42±0.03, P = 0.0058) was detected among them. The Ala allele of ATF6 Ala145Pro was significantly more frequent in the probands of early onset type 2 diabetic pedigrees (77.6% vs 69.4%, P = 0.0417). The Pro allele carriers had significantly lower high-density lipoprotein cholesterol levels (1.33±0.02 vs 1.25±0.02, P = 0.0140). For RBP4, we sequenced exons and the putative promoter region in 32 subjects to identify variants. Taking account of the pairwise linkage disequilibrium (LD) and minor allele frequencies, five SNPs were further genotyped in 255 type 2 diabetes patients and 372 normal controls. We found a rare haplotype CAA formed by +5388 C>T, +8201 T>A and +8204 T>A was more frequent in diabetic patients (P=0.0343, empirical P=0.0659). In the normal controls, the SNP +5388 C>T was associated with serum C-peptide levels at both fasting status (1.80±0.05 vs 1.56±0.07, P=0.0162) and 2-hours after glucose stimulation (7.15±0.26 vs 5.71±0.38, P=0.0075). The non-coding SNPs were also found to be associated with circulating RBP4 concentrations in both groups (P<0.05).
2. Evaluation the transferability of HapMap Chinese data in a Shanghai population
The HapMap project catalogs millions of common SNPs in the human genome in four major populations including northern Hans, with the aim to facilitate association studies on complex diseases. In this study, we used genotype data from International Type 2 Diabetes 1q Consortium to examine the transferability of HapMap Chinese data in Shanghai population. The HapMap Chinese data showed high consistence with Shanghai population on allele frequencies, LD coefficient r2 and haplotype frequencies (R=0.94, 0.97, 0.99 respectively, all P<0.0001). In addition, tagging SNP set selected from HapMap Chinese data also performed well in Shanghai population with the threshold 0.8 of r2 to cover 93.8% of the SNPs. The HapMap SNP data performed well in the Shanghai population and thus could be a powerful tool for the genetic studies on complex disease in southern Hans.
3. Positional cloning study of type 2 diabetes susceptible gene on chromosome 1q23.3 in Chinese
Previously, we detected a linkage signal of type 2 diabetes on chromosome 1q21-q25. International Type 2 Diabetes 1q Consortium then did a fine mapping analysis and located one of the susceptible genes on chromosome 1q23.3. In this study, we did a positional cloning study based on the previous linkage and fine mapping studies. Considering both LD and potential SNP function, 94 SNP were selected from HapMap data and genotyped in 1892 diabetic patients and 1808 normal controls using matrix-assisted laser desorption inoization-time of flight mass spectrometry. After quality control of genotyping, a total of 3491 individuals and 73 SNPs were analyzed. We found rs12742393, located in intron2 of NOS1AP, was associated with type 2 diabetes, C allele was significantly higher in the cases (25.2% vs 21.6%, P = 0.0004, empirical P = 0.0342). The haplotype TC formed by rs4531272 - rs12742393 was also significantly more frequent in the cases (52.6% vs 49.5%, P = 0.0092, empirical P = 0.0424). In the normal controls, rs1415263 was associated with serum levels of total cholesterol (TT vs TC vs CC: 5.13±0.06 vs 4.99±0.03 vs 4.94±0.09, P < 0.05) and low-density lipoprotein cholesterol (TT vs TC vs CC: 3.45±0.05 vs 3.36±0.03 vs 3.24±0.04, P < 0.05). We also found rs12029454 was associated with serum level of low-density lipoprotein cholesterol (GG vs GA vs AA: 3.27±0.03 vs 3.39±0.03 vs 3.46±0.07, P < 0.05).
引文
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