ACE、PAI-1基因多态性与2型糖尿病肾病的关系
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摘要
目的：探讨血管紧张素Ⅰ转换酶(Angiotensin Ⅰ converting enzyme，ACE)基因、血浆纤溶酶原激活物抑制剂(plasminogen activator inhibitor-1，PAI-I)基因多态性与2型糖尿病。肾病(diabetic nephropathy，DN)的相关性，并初步研究其可能机制。
方法：58例正常对照组、217例2型糖尿病，收集夜间8点至清晨8点的尿液，行尿白蛋白检测，同时行尿肌酐检测，计算尿白蛋白肌酐比值(albumn-to-creatinine ratio，ACR)，根据ACR比值将糖尿病组分为92例糖尿病非肾病、125例糖尿病肾病。提取DNA，聚合酶链反应扩增，产物以琼脂糖凝胶电泳分离确定ACE、PAI-1基因型。酶连免疫法(ELISA)测定空腹血浆PAI-1抗原量。并收集体重、身高、血压、血糖、糖基化血红蛋白、甘油三酯、胆固醇等资料，放免法测胰岛素，计算胰岛素敏感指数(insulin sensitivity，ISI)(ISI=1／(FBG×FIN)]、体重指数(body mass index，BMI)。
结果：1、检测出I、D两种ACE等位基因，其三种组合基因型Ⅱ、ID、DD。PAI-1检测出4G、5G两种PAI-1等位基因及其三种组合基因型4G／4G、4G／5G、5G/5G。2、正常人、糖尿病非肾病与糖尿病肾病组ACE基因型的分布有明显差别(X~2=57.459，p＜0.05)，糖尿病肾病组ACE基因中D等位基因频率明显高于糖尿病非肾病组(0.576：0.250，X~2=43.573，p＜0.05)。正常人、糖尿病非肾病与糖尿病肾病组相比，PAI-1基因型的分布有明显的差别(X~2=49.341，D＜0.05)，
糖尿病肾病组PA工一1基因中4G等位基因频率明显高于糖尿病非肾病组(0.576:
0.300，x，=3 1.480，p<0.05)。3、PAx一14e/4G基因型的视网膜病变的发病率明
显高于其它两组(P<0.05)。ACE基因具有D等位基因的患者血中的PAI一1明显
高于H型基因的患者(P<0.05)。以卜1基因具有4G等位基因的患者血中的以卜1
明显高于SG/SG型基因的患者(P<0.05)。4、血浆PAI一1与甘油三酷关系受以卜1
基因型的影响。4G/4G基因型PA工一1与甘油三酷相关性最强(r=0.43，p<0.05)。
5、Logistic回归分析表明ACE基因、PAI一1基因是2型糖尿病肾病的独立患病
风险因素。6、PAI一14G/4G型基因并ACED等位基因者比其它基因型具有更高的
糖尿病肾病发病危险。
讨论:1、2型糖尿病非肾病组ACE基因工等位基因频率高于2型糖尿病肾病
组，PAI一1基因5G等位基因频率高于2型糖尿病肾病组。ACE基因、PAI一1基因
分别是2型糖尿病肾病发病的独立患病风险因素，是2型糖尿病肾病发病的侯选
基因。2、ACE基因中携带D等位基因的血浆以I一1明显高于不携带D等位基因
者，PA工一1基因中携带4G等位基因的血浆PAI一1明显高于不携带4G等位基因者。
说明ACE基因、PA工一1基因可能参与PA工一1的基因表达作用。3、联合基因型中
以卜14G/4G型基因并ACED等位基因为糖尿病肾病发病的易感性基因。
[Objective] To investigate the frequency and functional significance of angiotensin I converting enzyme(ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphism and their relationship to type 2 diabetes with nephropathy.
[Methods) The allele frequency and the genotype distribution of the polymorphism of ACE gene and PAI-lgene in the group of 58 normal subjects and 217 type 2 diabetes were detected by means of polymerase chain reaction (PCR). According to measurement of the albumin-to-creatinine ratio(ACR) in overnight collection of the urine(8pm~8am), the group of type 2 diabetes was devided to diabetic nephropathy positive(DN+) group and diabetic nephropathy negative(DN-) group. PAI-1 antigen was quantified by a ELISA assay. Weight, height, arterial blood pressure, total cholesterol, triglycerids, HbA1C were measured. Insulin was determined with radio -immunoassay kit. Body mass index, insulin sensitivity were calculated.
[Results]1,2 alleles (I and D)and 3 genotypes(II, ID and DD)were detected in ACE gene. 2 alleles (4G and 5G)and 3 genotypes(5G/5G, 4G/5G and 4G/4G)were detected in PAI-1 gene. 2, The genotype distribution of the ACE gene polymorphism were different among normal subjects , patients with and without diabetic nephropathy (x2=57. 459 p < 0. 05), A higher prevalence of ACE D allele served among patients with diabetic nephropathy than those without(0. 576vsO.250, x2=43.573, p<0.05). the genotype distribution of the gene polymorphism were different among normal subjects, patients with and without diabetic nephropathy (x2=49. 341 p < 0. 05), A higher prevalence of PAI-1 4G allele served among patients with diabetic nephropathy than those without (0.576 vsO. 300, x2=31.480, p<0. 05). 3, A higher prevalence of diabetic retinopathy among patients with PAI-1 4G/4G genotype than those with PAI-14G/5G and 5G /5G genotypes( p< 0. 05). The patients with ACE D allele had more PAI-1 antigen than those with ACE II genotype (P<
0.05) . The patients with PAI-1 4G allele had more PAI-1 antigen than those with PAI-1 5G/5G genotypes (P < 0. 05) . 4, The association of PAI-1 antigen and serum triglycerids was effected by the PAI-1 genotypes, The PAI-1 antigen
serum triglycerids was effected by the PAI-1 genotypes, The PAI-1 antigen in the patients with PAI-1 4G/4G genotype was related to serum triglycerids (r=0. 43, p< 0. 05) . 5, Multiple logistic regression analysis of the risk factors associated with diabetic nephropathy revealed that the DD genotype of ACE gene and 4G/4G genotype of PAI-1 gene act as the independent risk factors for diabetic nephropathy.6, Coexistence of ACE D allele and PAI-14G/4G was associated with increased risk of type 2 diabetic nephropathy.
[Conclusion] 1, A higher prevalence of ACE DD genotype or D allele served among patients with diabetic nephropathy than those without. A higher prevalence of PAI-1 4G/4G genotype or 4G allele served among patients with diabetic nephropathy than those without. The DD genotype of ACE gene and 4G/4G genotype of PAI-1 gene acted as the independent risk factors for diabetic nephropathy. 2, The patients with ACE D allele had more PAI-1 antigen than those with I allele. The patients with PAI-1 4G allele had more PAI-1 antigen than those with 5G allele. In this report, we have demonstrated that the ACE and PAI-1 genotype could effect PAI-1 gene expression. 3, The presence of combinations of ACE D allele and PAI-1 4G/4G may involved in the generation of diabetic nephropathy.
方法：58例正常对照组、217例2型糖尿病，收集夜间8点至清晨8点的尿液，行尿白蛋白检测，同时行尿肌酐检测，计算尿白蛋白肌酐比值(albumn-to-creatinine ratio，ACR)，根据ACR比值将糖尿病组分为92例糖尿病非肾病、125例糖尿病肾病。提取DNA，聚合酶链反应扩增，产物以琼脂糖凝胶电泳分离确定ACE、PAI-1基因型。酶连免疫法(ELISA)测定空腹血浆PAI-1抗原量。并收集体重、身高、血压、血糖、糖基化血红蛋白、甘油三酯、胆固醇等资料，放免法测胰岛素，计算胰岛素敏感指数(insulin sensitivity，ISI)(ISI=1／(FBG×FIN)]、体重指数(body mass index，BMI)。
结果：1、检测出I、D两种ACE等位基因，其三种组合基因型Ⅱ、ID、DD。PAI-1检测出4G、5G两种PAI-1等位基因及其三种组合基因型4G／4G、4G／5G、5G/5G。2、正常人、糖尿病非肾病与糖尿病肾病组ACE基因型的分布有明显差别(X~2=57.459，p＜0.05)，糖尿病肾病组ACE基因中D等位基因频率明显高于糖尿病非肾病组(0.576：0.250，X~2=43.573，p＜0.05)。正常人、糖尿病非肾病与糖尿病肾病组相比，PAI-1基因型的分布有明显的差别(X~2=49.341，D＜0.05)，
糖尿病肾病组PA工一1基因中4G等位基因频率明显高于糖尿病非肾病组(0.576:
0.300，x，=3 1.480，p<0.05)。3、PAx一14e/4G基因型的视网膜病变的发病率明
显高于其它两组(P<0.05)。ACE基因具有D等位基因的患者血中的PAI一1明显
高于H型基因的患者(P<0.05)。以卜1基因具有4G等位基因的患者血中的以卜1
明显高于SG/SG型基因的患者(P<0.05)。4、血浆PAI一1与甘油三酷关系受以卜1
基因型的影响。4G/4G基因型PA工一1与甘油三酷相关性最强(r=0.43，p<0.05)。
5、Logistic回归分析表明ACE基因、PAI一1基因是2型糖尿病肾病的独立患病
风险因素。6、PAI一14G/4G型基因并ACED等位基因者比其它基因型具有更高的
糖尿病肾病发病危险。
讨论:1、2型糖尿病非肾病组ACE基因工等位基因频率高于2型糖尿病肾病
组，PAI一1基因5G等位基因频率高于2型糖尿病肾病组。ACE基因、PAI一1基因
分别是2型糖尿病肾病发病的独立患病风险因素，是2型糖尿病肾病发病的侯选
基因。2、ACE基因中携带D等位基因的血浆以I一1明显高于不携带D等位基因
者，PA工一1基因中携带4G等位基因的血浆PAI一1明显高于不携带4G等位基因者。
说明ACE基因、PA工一1基因可能参与PA工一1的基因表达作用。3、联合基因型中
以卜14G/4G型基因并ACED等位基因为糖尿病肾病发病的易感性基因。
[Objective] To investigate the frequency and functional significance of angiotensin I converting enzyme(ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphism and their relationship to type 2 diabetes with nephropathy.
[Methods) The allele frequency and the genotype distribution of the polymorphism of ACE gene and PAI-lgene in the group of 58 normal subjects and 217 type 2 diabetes were detected by means of polymerase chain reaction (PCR). According to measurement of the albumin-to-creatinine ratio(ACR) in overnight collection of the urine(8pm~8am), the group of type 2 diabetes was devided to diabetic nephropathy positive(DN+) group and diabetic nephropathy negative(DN-) group. PAI-1 antigen was quantified by a ELISA assay. Weight, height, arterial blood pressure, total cholesterol, triglycerids, HbA1C were measured. Insulin was determined with radio -immunoassay kit. Body mass index, insulin sensitivity were calculated.
[Results]1,2 alleles (I and D)and 3 genotypes(II, ID and DD)were detected in ACE gene. 2 alleles (4G and 5G)and 3 genotypes(5G/5G, 4G/5G and 4G/4G)were detected in PAI-1 gene. 2, The genotype distribution of the ACE gene polymorphism were different among normal subjects , patients with and without diabetic nephropathy (x2=57. 459 p < 0. 05), A higher prevalence of ACE D allele served among patients with diabetic nephropathy than those without(0. 576vsO.250, x2=43.573, p<0.05). the genotype distribution of the gene polymorphism were different among normal subjects, patients with and without diabetic nephropathy (x2=49. 341 p < 0. 05), A higher prevalence of PAI-1 4G allele served among patients with diabetic nephropathy than those without (0.576 vsO. 300, x2=31.480, p<0. 05). 3, A higher prevalence of diabetic retinopathy among patients with PAI-1 4G/4G genotype than those with PAI-14G/5G and 5G /5G genotypes( p< 0. 05). The patients with ACE D allele had more PAI-1 antigen than those with ACE II genotype (P<
0.05) . The patients with PAI-1 4G allele had more PAI-1 antigen than those with PAI-1 5G/5G genotypes (P < 0. 05) . 4, The association of PAI-1 antigen and serum triglycerids was effected by the PAI-1 genotypes, The PAI-1 antigen
serum triglycerids was effected by the PAI-1 genotypes, The PAI-1 antigen in the patients with PAI-1 4G/4G genotype was related to serum triglycerids (r=0. 43, p< 0. 05) . 5, Multiple logistic regression analysis of the risk factors associated with diabetic nephropathy revealed that the DD genotype of ACE gene and 4G/4G genotype of PAI-1 gene act as the independent risk factors for diabetic nephropathy.6, Coexistence of ACE D allele and PAI-14G/4G was associated with increased risk of type 2 diabetic nephropathy.
[Conclusion] 1, A higher prevalence of ACE DD genotype or D allele served among patients with diabetic nephropathy than those without. A higher prevalence of PAI-1 4G/4G genotype or 4G allele served among patients with diabetic nephropathy than those without. The DD genotype of ACE gene and 4G/4G genotype of PAI-1 gene acted as the independent risk factors for diabetic nephropathy. 2, The patients with ACE D allele had more PAI-1 antigen than those with I allele. The patients with PAI-1 4G allele had more PAI-1 antigen than those with 5G allele. In this report, we have demonstrated that the ACE and PAI-1 genotype could effect PAI-1 gene expression. 3, The presence of combinations of ACE D allele and PAI-1 4G/4G may involved in the generation of diabetic nephropathy.
引文
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2. Wong TY, Poon P, Szeto CC, et al. Association of plasminogen activator inhibitor-1 4G/5G genotype and type 2 diabetic nephropathy in Chinese patients. Kidney Int, 2000,57:632-642.
3. American Diabetes Association. Diabetic Nephropathy. Diabetes Care, 2002, 25:85-89.
4．吴红梅，屈燧林，邓珏林，等。血管紧张素Ⅰ转换酶基因多态性与非胰岛素依赖性糖尿病肾病的相关性。中华遗传学杂志，1999，16：173-175．
5．李长贵，董硕虎，王海燕，等。PAI-1基因多态性与2型糖尿病肾病的相关性研究。中国糖尿病杂志，2001，9：333-340。
6．毛红，余洁。t-PhA、PAI-1活性测定在糖尿病肾病临床中的意义。临床血液学杂志，2000．13：116-117。
7. Roger K, Joachim S, Carolein A H P, et al. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol, 1999, 19:1623 - 1629.
8．陈香美。凝血酶上调人肾小球系膜细胞PAI-1表达的细胞内信号转导研究。解放军医学，1999，24：157-159。
9．刘亚军。TGF-β1、PAI-1与糖尿病肾病。国外医学·泌尿系统分册，2000，20：107-109。
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11. Wong AP,Cortez SL, Baricos WH, et al.Role of plasmin and gelatinase in extracellular matrix degradation by culture rat mesingial cells. Am J Physiol, 1992,263:1112-1118.
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39. Maurizio M, Giuseppe C, Marina d'A, et al. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis relation to environmental and genetic determinants.Arterioscler, Thromb, Vasc Biol, 1998,18:562-567.
40. Eriksson P, Kallin B, van t'HooftFM, et al. Allelic-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A, 1995, 92:1851 - 1855.
41. Nagi DK,Mccormacl LJ, Mohamed-Ali V, et al. Diabetic Retinopathy, primoter (4G/5G)polymorphism of PAI-1 gene, and PAI-1 activity in pima Indians with type 2 diabetes. Diabetes Care, 1997,20:13-20.
2. Wong TY, Poon P, Szeto CC, et al. Association of plasminogen activator inhibitor-1 4G/5G genotype and type 2 diabetic nephropathy in Chinese patients. Kidney Int, 2000,57:632-642.
3. American Diabetes Association. Diabetic Nephropathy. Diabetes Care, 2002, 25:85-89.
4．吴红梅，屈燧林，邓珏林，等。血管紧张素Ⅰ转换酶基因多态性与非胰岛素依赖性糖尿病肾病的相关性。中华遗传学杂志，1999，16：173-175．
5．李长贵，董硕虎，王海燕，等。PAI-1基因多态性与2型糖尿病肾病的相关性研究。中国糖尿病杂志，2001，9：333-340。
6．毛红，余洁。t-PhA、PAI-1活性测定在糖尿病肾病临床中的意义。临床血液学杂志，2000．13：116-117。
7. Roger K, Joachim S, Carolein A H P, et al. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol, 1999, 19:1623 - 1629.
8．陈香美。凝血酶上调人肾小球系膜细胞PAI-1表达的细胞内信号转导研究。解放军医学，1999，24：157-159。
9．刘亚军。TGF-β1、PAI-1与糖尿病肾病。国外医学·泌尿系统分册，2000，20：107-109。
10. Baricos WH, Cortez SL, EL-Dahr SS, et al. ECM degradation by cultured human mesangial cells is mediated by a PA/plasmin/MMP-2cadcade. Kidney Int, 1995,47:1039-1047.
11. Wong AP,Cortez SL, Baricos WH, et al.Role of plasmin and gelatinase in extracellular matrix degradation by culture rat mesingial cells. Am J Physiol, 1992,263:1112-1118.
12. Schmidt S, Strojek K, Grzeszczak W, et al. Excess of DD homozygotes in haemodialysed patients with type Ⅱ diabetes. The Diabetic Nephropathy Study Group. Nephrol. Dial. Transplant, 1997, 12:427 - 429.
13. Marre M, Bernadet P, Gallois Y, et al. Relationships between angiotensin Ⅰ converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Diabetes, 1994,43:384-388.
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