基质金属蛋白酶-9基因多态性与2型糖尿病血管并发症的相关性研究
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摘要
目的：通过检测天津地区汉族2型糖尿病患者和正常人群中MMP-9基因启动子区C-1562-T基因多态性的分布频率分析这种基因多态性与糖尿病大、微血管并发症的相关性。
方法：随机收集288名相互无亲缘关系的2型糖尿病患者(实验组)及120名健康对照者(正常对照组)的空腹血液标本，从外周血白细胞中获得基因组DNA，利用PCR-RFLP方法对MMP-9基因启动子区C-1562-T位点基因型进行测定。
结果：1．实验组中MMP-9 C-1562-T基因位点发现C、T两种等位基因和CC、CT、TT三种基因型：但在正常对照组中未检测到TT基因型，实验组中TT基因型仅发现6例，统计学分析显示实验组和正常对照组间这两种等位基因和三种基因型的分布无差异。
2．在实验组中，2型糖尿病无大血管病变组与合并大血管病变组比较CC基因型与C等位基因显著增加(P＜0.01)；在分别对糖尿病合并冠心病、下肢动脉硬化闭塞症的分析中发现与合并这两种并发症者相比，无相应并发症组的CC基因型与C等位基因均增加(P＜0.05)；但合并脑血管病变组与无脑血管病变组比较，增加趋势无显著性差异(P＞0.05)。
3．在2型糖尿病合并肾病不同时期各组间C-1562-T基因多态性基因型和等位基因分布的分析中可见糖尿病微量蛋白尿组中T等位基因明显减少；大量蛋白尿组与无并发症组T等位基因频率相似。
4．在对2型糖尿病合并肾病和大血管病变的综合分析显示：CT+TT基因型与T等位基因频率在糖尿病单纯合并肾病组最低，糖尿病单纯合并大血管并发症组最高，合并两种并发症组与无并发症组两组间相似。且TT基因型仅分布于合并大血管病变的两组中。
5．2型糖尿病无视网膜并发症组、糖尿病背景型视网膜并发症组、糖
天津医科大学硕士论文摘要
尿病增殖型视网膜并发症组三组间T等位基因和CT，T’T基因型频率
逐渐增加，但差异不显著。
6.在对糖尿病合并肾病和视网膜病变的综合分析显示:CT十TT基因
型与T等位基因频率在糖尿病单纯合并肾病组最低，糖尿病单纯合
并视网膜并发症组最高，合并两种并发症组略高于无并发症组，但
差异不显著。
结论:1 .2型糖尿病与正常人群中MMP一9基因启动子区C一1562一T基因位点
CT和，I’T基因型与C、T等位基因频率分布相同。
2.在2型糖尿病人群中，CC基因型与C等位基因在糖尿病无大血管
病变者中显著升高，可能是糖尿病大血管病变的保护型基因。
3.在2型糖尿病人群中，CT和TT基因型与T等位基因在糖尿病单纯
合并肾病者中显著减少，T等位基因可能是DN的保护型基因
4.2型糖尿病合并视网膜病变者特别是增殖性视网膜病变患者中CT
和TT基因型与T等位基因频率增加，但差异不显著，尚需进一步的
大量样本的相关研究
5.由于2型糖尿病及其慢性并发症是一种遗传基因和内外环境综合作
用而形成的多种病理过程参与的复杂的综合征，2型糖尿病本身特殊
的糖脂代谢紊乱状态在其慢性并发症的发生中起了同样重要的且更
为复杂的作用。
Abstract
The MMPs constitute a family of endopeptidases that have in common the presence of zinc in their active site, a dependency on Ca2+ for their activity. The MMPs can degrade all kinds of contents of ECM except polyglycan , and contribute to cell proliferation , neovascularogenesis and tissue remodeling and so on , so they participate in the processes of various pathophysiology in vivo . As one of the most important members , the substrates of MMP-9 are the main contents of vascular basement membrane and extracellular matrix , so its expression level and the change of activation have been attached much importance to vascular disease .In recent studies , it has been found that C-1562-T allele gene polymorphism in the promoter region of MMP-9 gene are both associated with the gene transcriptional activation , and its activities have relationships with the vascular complications of T2DM . Objective
To investigate the relationships between C-1562-T allele gene polymorphism and the macro- and micro vascular complications of T2DM in Tianjin. Methods
Fasting blood sample of 288 T2DM patients and 120 health controls who were unrelative were collected randomly , the genome DNA was obtained from the leukocytes , and then PCR-RFLP method was performed to investigate the genotype of MMP-9 gene promoter C-1562-T site. Results
1. C,T alleles and CC,CT,TT genotypes were found in T2DM subject, but we failed to get TT genotype in normal control group. From the statistic data , we found that there was no difference between type 2 diabetic group and the normal control group in the frequency of the two alleles and the three genotypes .
6
Abstract
2. In the type 2 diabetic group, C allele and CC genotypes of diabetes without macroangiopathy group were significantly increased than those of diabetes with macroangiopathy group; there were the similar tendency in the respective analyses of CHD,ASO and CVD; but there was no statistically differency in CVD group.
3. A decreased frequency of T allele was observed in type 2 diabetes with microalbuminuria as compared with T2DM without nephropathy or T2DM with clinical proteinuria; and the frequency of T allele in the latter two groups were similar.
4. General analysis of T2DM with nephropathy or macroangiopathy shows that the lowest frequency of T allele and CT,TT genotypes in the group of type 2diabetes simple with nephropathy, the highest frequency in the group of type 2diabetes simple with macroangiopathy and the frequency of those in the group of type 2diabetes with both complications was similar with that of without the two complications. What's more ,TT genotype was found only in the two groups with macroangiopathy.
5. T allele frequency was increased gradually in non-DR ,BDR and PDR group groups ,but there were no significant difference.
6. Genernal analysis of type 2 diabetes with DN and DR indicates that T allele and CT,TT genotype frequency were the lowest in type 2 diabetes simple with DN group , highest in type 2 diabetes simple with DR group, the frequency of those in the group of type 2diabetes with both complications was similar with that of without the two complications,but the statistical difference was not reached.
Conclusion
l.C,T allele and CC,CT,TT genotypes frequencies were same in normal
Abstract
control group and T2DM groups.
2. In T2DM group, the frequencies of C allele and CC genotypes were markedly increased in T2DM without macroangiopathy , therefore C allele may be the protective gene of diabetic macroangiopathy(P=0.001).
3. T allele and CT,TT genotypes frequencies were significantly decreased in T2DM simple with nephropathy , therefore T allele may be the protective gene of DN(P=0.001).
4. T allele and CT,TT genotypes frequencies were increased in T2DM with retinopathy , especially proliferative retinopathy , but there was no statistical difference.
5. T2DM and its chronic complications were a kind of complicated syndrome affected by gene and environment factors in vivo and in vitro involving various pathological processes. The char
方法：随机收集288名相互无亲缘关系的2型糖尿病患者(实验组)及120名健康对照者(正常对照组)的空腹血液标本，从外周血白细胞中获得基因组DNA，利用PCR-RFLP方法对MMP-9基因启动子区C-1562-T位点基因型进行测定。
结果：1．实验组中MMP-9 C-1562-T基因位点发现C、T两种等位基因和CC、CT、TT三种基因型：但在正常对照组中未检测到TT基因型，实验组中TT基因型仅发现6例，统计学分析显示实验组和正常对照组间这两种等位基因和三种基因型的分布无差异。
2．在实验组中，2型糖尿病无大血管病变组与合并大血管病变组比较CC基因型与C等位基因显著增加(P＜0.01)；在分别对糖尿病合并冠心病、下肢动脉硬化闭塞症的分析中发现与合并这两种并发症者相比，无相应并发症组的CC基因型与C等位基因均增加(P＜0.05)；但合并脑血管病变组与无脑血管病变组比较，增加趋势无显著性差异(P＞0.05)。
3．在2型糖尿病合并肾病不同时期各组间C-1562-T基因多态性基因型和等位基因分布的分析中可见糖尿病微量蛋白尿组中T等位基因明显减少；大量蛋白尿组与无并发症组T等位基因频率相似。
4．在对2型糖尿病合并肾病和大血管病变的综合分析显示：CT+TT基因型与T等位基因频率在糖尿病单纯合并肾病组最低，糖尿病单纯合并大血管并发症组最高，合并两种并发症组与无并发症组两组间相似。且TT基因型仅分布于合并大血管病变的两组中。
5．2型糖尿病无视网膜并发症组、糖尿病背景型视网膜并发症组、糖
天津医科大学硕士论文摘要
尿病增殖型视网膜并发症组三组间T等位基因和CT，T’T基因型频率
逐渐增加，但差异不显著。
6.在对糖尿病合并肾病和视网膜病变的综合分析显示:CT十TT基因
型与T等位基因频率在糖尿病单纯合并肾病组最低，糖尿病单纯合
并视网膜并发症组最高，合并两种并发症组略高于无并发症组，但
差异不显著。
结论:1 .2型糖尿病与正常人群中MMP一9基因启动子区C一1562一T基因位点
CT和，I’T基因型与C、T等位基因频率分布相同。
2.在2型糖尿病人群中，CC基因型与C等位基因在糖尿病无大血管
病变者中显著升高，可能是糖尿病大血管病变的保护型基因。
3.在2型糖尿病人群中，CT和TT基因型与T等位基因在糖尿病单纯
合并肾病者中显著减少，T等位基因可能是DN的保护型基因
4.2型糖尿病合并视网膜病变者特别是增殖性视网膜病变患者中CT
和TT基因型与T等位基因频率增加，但差异不显著，尚需进一步的
大量样本的相关研究
5.由于2型糖尿病及其慢性并发症是一种遗传基因和内外环境综合作
用而形成的多种病理过程参与的复杂的综合征，2型糖尿病本身特殊
的糖脂代谢紊乱状态在其慢性并发症的发生中起了同样重要的且更
为复杂的作用。
Abstract
The MMPs constitute a family of endopeptidases that have in common the presence of zinc in their active site, a dependency on Ca2+ for their activity. The MMPs can degrade all kinds of contents of ECM except polyglycan , and contribute to cell proliferation , neovascularogenesis and tissue remodeling and so on , so they participate in the processes of various pathophysiology in vivo . As one of the most important members , the substrates of MMP-9 are the main contents of vascular basement membrane and extracellular matrix , so its expression level and the change of activation have been attached much importance to vascular disease .In recent studies , it has been found that C-1562-T allele gene polymorphism in the promoter region of MMP-9 gene are both associated with the gene transcriptional activation , and its activities have relationships with the vascular complications of T2DM . Objective
To investigate the relationships between C-1562-T allele gene polymorphism and the macro- and micro vascular complications of T2DM in Tianjin. Methods
Fasting blood sample of 288 T2DM patients and 120 health controls who were unrelative were collected randomly , the genome DNA was obtained from the leukocytes , and then PCR-RFLP method was performed to investigate the genotype of MMP-9 gene promoter C-1562-T site. Results
1. C,T alleles and CC,CT,TT genotypes were found in T2DM subject, but we failed to get TT genotype in normal control group. From the statistic data , we found that there was no difference between type 2 diabetic group and the normal control group in the frequency of the two alleles and the three genotypes .
6
Abstract
2. In the type 2 diabetic group, C allele and CC genotypes of diabetes without macroangiopathy group were significantly increased than those of diabetes with macroangiopathy group; there were the similar tendency in the respective analyses of CHD,ASO and CVD; but there was no statistically differency in CVD group.
3. A decreased frequency of T allele was observed in type 2 diabetes with microalbuminuria as compared with T2DM without nephropathy or T2DM with clinical proteinuria; and the frequency of T allele in the latter two groups were similar.
4. General analysis of T2DM with nephropathy or macroangiopathy shows that the lowest frequency of T allele and CT,TT genotypes in the group of type 2diabetes simple with nephropathy, the highest frequency in the group of type 2diabetes simple with macroangiopathy and the frequency of those in the group of type 2diabetes with both complications was similar with that of without the two complications. What's more ,TT genotype was found only in the two groups with macroangiopathy.
5. T allele frequency was increased gradually in non-DR ,BDR and PDR group groups ,but there were no significant difference.
6. Genernal analysis of type 2 diabetes with DN and DR indicates that T allele and CT,TT genotype frequency were the lowest in type 2 diabetes simple with DN group , highest in type 2 diabetes simple with DR group, the frequency of those in the group of type 2diabetes with both complications was similar with that of without the two complications,but the statistical difference was not reached.
Conclusion
l.C,T allele and CC,CT,TT genotypes frequencies were same in normal
Abstract
control group and T2DM groups.
2. In T2DM group, the frequencies of C allele and CC genotypes were markedly increased in T2DM without macroangiopathy , therefore C allele may be the protective gene of diabetic macroangiopathy(P=0.001).
3. T allele and CT,TT genotypes frequencies were significantly decreased in T2DM simple with nephropathy , therefore T allele may be the protective gene of DN(P=0.001).
4. T allele and CT,TT genotypes frequencies were increased in T2DM with retinopathy , especially proliferative retinopathy , but there was no statistical difference.
5. T2DM and its chronic complications were a kind of complicated syndrome affected by gene and environment factors in vivo and in vitro involving various pathological processes. The char
引文
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2．鲁衍强，叶其壮。基质金属蛋白酶及其抑制剂。生命的化学．2002，22(4)：348-350。
3. Esther E.J.M. Creemers, Jack EM. Cleutjens, Jos EM. Smits, er al. Matrix Metalloproteinase Inhibition After Myocardial Infarction A New Approach to Prevent Heart Failure? Circulation Research. 2001; 89: 201.
4. Kleiner DE, Stetler-Stevenson WG. Structural biochemistry and activation of matrix metalloproteinases. Curr Opin Cell Biol 1993; 5: 891-897.
5. Maedn H, Okamoto T, Akaike T. Human matrix metalloprotease activation by insults of bacterial infection involving proteases and free radicals. Biol Chem. 1998; 379: 193-200.
6. Benhow U, Brinckerhoff C. The AP-1 site and MMP gene regulation: what is all the fuss about. Matrix Biol, 1997, 15: 519-526.
7. Schutte J, Viallet J, Nau M, Segal S, Fedorko J, Minna J: junB inhibits and c-fos stimulates the transforming and trans-aetivating activities of c-jun. Cell. 1989, 59: 987-999.
8. Mclennan, Susan V.. Fisher, Elizabeth. Martell, et al. Effects of glucose on matrix metalloproteinase and plasmin activities in mesangial cells: Possible role in diabetic nephROPathy. Kidney International-Supplement. Diabetic Kidney Disease Research at the Turn of the Century. 58 Supplement No. 77: S-81-S-87, September 2000.
9. Murphy G, Willenbroek F, Crabbe T, et al. Regulation of matrix metalloproteinase activity. Ann N Y Acad Sci.. 1994; 732: 31-41.
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