血管紧张素转换酶（ACE）基因多态性及其它因素与2型糖尿病肾病关系的配对病例对照研究
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摘要
目的：探讨ACE基因第16内含子的Alu序列插入／缺失(I／D)多态性及其它因素与2型糖尿病肾病(DN)的关系。
方法：采用以医院为基础的配对病例对照研究方法，对101对研究对象进行了研究。病例为2001年11月至2003年1月在天津医科大学代谢病医院住院的2型糖尿病肾病患者，对照为同期、在该医院住院的未合并肾病的2型糖尿病(DM)患者，配比条件为年龄和性别。对病例和对照使用统一的调查表进行调查，内容包括：人口统计学特征、疾病史、疾病家族史、饮食习惯、行为方式、社会心理因素以及体格检查和实验室检查等资料。应用聚合酶链反应(PCR)及琼脂糖凝胶电泳方法进行ACE基因多态性分析。采用条件logistic回归模型对DN的危险因素进行单因素和多因素分析。
结果：单因素条件logistic回归分析结果表明：ACE基因第16内含子的Alu序列插入／缺失(I／D)多态性与DN的发生之间有统计学关联，D等位基因的出现使DN发生的相对危险增加，与Ⅱ基因型相比，基因型为ID、DD的DM患者并发DN的OR值及其95％可信区间分别为2.419(95％CI：1.180～4.959)和3.417(95％CI：1.608～7.260)；经DM家族史、高血压史调整后，其统计学显著性仍然存在。单因素分析结果表明：文化程度、DM病程、血糖控制程度、DM家族史、既往高血压史、既往高血压治疗情况、豆类摄入、血清肌酐水平和血清高密度脂蛋白胆固醇水平与DN的发生有统计学关联，OR值及其95％可信区间分别为0.400(95％CI：0.176～0.908)、1.907(95％CI：1.399～2.601)、1.553(95％CI：1.033～2.337)、2.000(95％CI：1.097～3.644)、
天津瞥澎比笋颐毖笋世艘丈
2 .055(95%Cl:1.170~3.610)、1.540(1.123一2.111)、1.359(95%Cl是
1 .010~1.828)、4.000(95%Cl:1.927~8.304)和0.390(95%Cl:0.164~
0.924)。但是，经调整可能的混杂因素的作用后，文化程度、血糖控制情况、
既往高血压治疗情况、高密度脂蛋白胆固醇水平等与DN发生之间的关系失去
统计学意义。未发现高血压家族史、冠心病家族史、体育锻炼情况、吸烟、
饮酒、饮茶、肉类摄入、蛋类摄入、奶类摄入、油脂摄入、蔬菜摄入、甜食
摄入、怀孕次数、生产巨大儿史、性格特点、工作和生活中的不良应激事件、
重大不幸生活事件、曾患有其他重大疾病或意外创伤、调查时体质指数以及
血清总胆固醇、甘油三酷、低密度脂蛋白胆固醇和极低密度脂蛋白胆固醇水
平与DN的发生之间有统计学关联。ACE基因型与DM病程之间的交互作用
与DN发生之间的关联有统计学意义(OR=1 .741，95%cI:1.107~2.740)，
ACE基因D等位基因和DM病程长同时存在的情况下，DN发生的危险性更大。
多因素条件logistie回归分析结果显示，ACE基因型(OR二1.890，95%Cl:
1.146一3.118)、DM病程(OR=2.302，95%Cl:1.507~3.515)、豆类摄入
(OR二1.629，95%Cl:1.054~2.519)和血清肌配水平(OR=5.918，95忧I:2.224~
15.750)为DN的独立危险因素。未发现ACE基因I/D多态性与DN病情轻重(DN
分期)之间有统计学关联。
结论:ACE基因的D等位基因为DN的独立预报因子，DM病程长、豆
类摄入多和血清肌醉水平高均可增加DN发生的危险性。
Objectives: The aim of this study was to explore the associations between insertion/deletion (I/D) polymorphism of Alu sequence at intron 16 of the polymorphism of angiotensin-converting enzyme (ACE) gene and other factors and diabetic nephropathy(DN) in type 2 diabetic patients.
Methods: A hospital-based case-control study was conducted in Tianjin from November 2001 to January 2003. 101 pairs of subjects were recruited. The cases were considered to be DN patients and the controls were considered to be type 2 diabetic patients (DM) without diabetic nephropathy. Each case was matched with one control on sex and age. Information was collected through face-to-face interview, which included demographic data, disease history, disease family history, dietetic habit, behavior pattern, social psychologic character, clinical data and laboratory data. I/D polymorphism of ACE gene was assessed by polymerase chain reaction (PCR) and the PCR products were subjected to electrophoresis on agarose gel that was stained with ethidium bromide. Using the conditional logistic regression model, we examined the effect of the collected factors on the risk of the diabetic nephropathy development. Results: Results from univariate conditional logistic regression analysis showed
that the I/D polymorphism of ACE gene was associated with development of diabetic nephropathy. D allele was more frequency among DN patients. Compared with the group of II genotype, the corresponding OR with 95% CI of the groups of ID genotype and DD genotype were 2.419( 1.180~4.959)and 3.417 (1.608~7.260) respectively. After adjusting for diabetic family history and history of hypertension, the results still showed that the association between ACE genotype and DN was statistically significant. Results from univariate conditional logistic regression analysis also showed that DN was associated with education level, diabetes duration, glycemia control, diabetic family history, history of hypertension, hypertension treatment, legume intake, serum creatinine level and serum level of high density lipoprotein (HDL) cholesterol. The corresponding OR with 95% CI were 0.400(0.176-0.908), 1.907(1.399-2.601), 1.553(1.033-2.337), 2.000(1.097-3.644), 2.055(1.170-3.610), 1.540(1.123-2.111), 1.359 (1.010-1.828), 4.000(1.927-8.304) and 0.390(0.164-0.924) respectively. However, after adjusting for possible confounding factors, the associations between these factors, including education level, glycemia control, hypertension treatment and serum HDL cholesterol level, and DN were statistically significant. No associations were observed between the following factors and DN, which were family history of hypertension, family history of coronary heart disease, exercise, smoking, alcohol drinking, tea drinking, meat intake, egg intake, milk intake, fat intake, vegetable intake, sweetmeat intake, times of pregnancy, the history of delivering macrosomia, character, body index, serum total cholesterol, triglycerides, low density lipoprotein and very low density lipoprotein cholesterol levels. ACE genotype and diabetes duration were found to have an interaction(OR=1.741, 95%CI:1.107 -2.740). When subjected to multivariate conditional logistic regression analysis, four factors remained statistical
associations with DN, which were ACE genotype(OR=1.890, 95%CI:1.146~ 3.118), diabetes duration(OR=2.302, 95%CI:1.507 ~ 3.515), legume intake (OR=1.629, 95%CI:1.054~ 2.519) and serum creatinine level (OR=5.918, 95%CI:2.224~ 15.750). No association was observed between I/D polymorphism of ACE gene and DN stage.
Conclusion: D allele of ACE gene was an independent predictive factor for diabetic nephropathy, long diabetes duration, increased legume intake and high serum creatinine level were associated with higher risk for the development of diabetic nephropathy.
方法：采用以医院为基础的配对病例对照研究方法，对101对研究对象进行了研究。病例为2001年11月至2003年1月在天津医科大学代谢病医院住院的2型糖尿病肾病患者，对照为同期、在该医院住院的未合并肾病的2型糖尿病(DM)患者，配比条件为年龄和性别。对病例和对照使用统一的调查表进行调查，内容包括：人口统计学特征、疾病史、疾病家族史、饮食习惯、行为方式、社会心理因素以及体格检查和实验室检查等资料。应用聚合酶链反应(PCR)及琼脂糖凝胶电泳方法进行ACE基因多态性分析。采用条件logistic回归模型对DN的危险因素进行单因素和多因素分析。
结果：单因素条件logistic回归分析结果表明：ACE基因第16内含子的Alu序列插入／缺失(I／D)多态性与DN的发生之间有统计学关联，D等位基因的出现使DN发生的相对危险增加，与Ⅱ基因型相比，基因型为ID、DD的DM患者并发DN的OR值及其95％可信区间分别为2.419(95％CI：1.180～4.959)和3.417(95％CI：1.608～7.260)；经DM家族史、高血压史调整后，其统计学显著性仍然存在。单因素分析结果表明：文化程度、DM病程、血糖控制程度、DM家族史、既往高血压史、既往高血压治疗情况、豆类摄入、血清肌酐水平和血清高密度脂蛋白胆固醇水平与DN的发生有统计学关联，OR值及其95％可信区间分别为0.400(95％CI：0.176～0.908)、1.907(95％CI：1.399～2.601)、1.553(95％CI：1.033～2.337)、2.000(95％CI：1.097～3.644)、
天津瞥澎比笋颐毖笋世艘丈
2 .055(95%Cl:1.170~3.610)、1.540(1.123一2.111)、1.359(95%Cl是
1 .010~1.828)、4.000(95%Cl:1.927~8.304)和0.390(95%Cl:0.164~
0.924)。但是，经调整可能的混杂因素的作用后，文化程度、血糖控制情况、
既往高血压治疗情况、高密度脂蛋白胆固醇水平等与DN发生之间的关系失去
统计学意义。未发现高血压家族史、冠心病家族史、体育锻炼情况、吸烟、
饮酒、饮茶、肉类摄入、蛋类摄入、奶类摄入、油脂摄入、蔬菜摄入、甜食
摄入、怀孕次数、生产巨大儿史、性格特点、工作和生活中的不良应激事件、
重大不幸生活事件、曾患有其他重大疾病或意外创伤、调查时体质指数以及
血清总胆固醇、甘油三酷、低密度脂蛋白胆固醇和极低密度脂蛋白胆固醇水
平与DN的发生之间有统计学关联。ACE基因型与DM病程之间的交互作用
与DN发生之间的关联有统计学意义(OR=1 .741，95%cI:1.107~2.740)，
ACE基因D等位基因和DM病程长同时存在的情况下，DN发生的危险性更大。
多因素条件logistie回归分析结果显示，ACE基因型(OR二1.890，95%Cl:
1.146一3.118)、DM病程(OR=2.302，95%Cl:1.507~3.515)、豆类摄入
(OR二1.629，95%Cl:1.054~2.519)和血清肌配水平(OR=5.918，95忧I:2.224~
15.750)为DN的独立危险因素。未发现ACE基因I/D多态性与DN病情轻重(DN
分期)之间有统计学关联。
结论:ACE基因的D等位基因为DN的独立预报因子，DM病程长、豆
类摄入多和血清肌醉水平高均可增加DN发生的危险性。
Objectives: The aim of this study was to explore the associations between insertion/deletion (I/D) polymorphism of Alu sequence at intron 16 of the polymorphism of angiotensin-converting enzyme (ACE) gene and other factors and diabetic nephropathy(DN) in type 2 diabetic patients.
Methods: A hospital-based case-control study was conducted in Tianjin from November 2001 to January 2003. 101 pairs of subjects were recruited. The cases were considered to be DN patients and the controls were considered to be type 2 diabetic patients (DM) without diabetic nephropathy. Each case was matched with one control on sex and age. Information was collected through face-to-face interview, which included demographic data, disease history, disease family history, dietetic habit, behavior pattern, social psychologic character, clinical data and laboratory data. I/D polymorphism of ACE gene was assessed by polymerase chain reaction (PCR) and the PCR products were subjected to electrophoresis on agarose gel that was stained with ethidium bromide. Using the conditional logistic regression model, we examined the effect of the collected factors on the risk of the diabetic nephropathy development. Results: Results from univariate conditional logistic regression analysis showed
that the I/D polymorphism of ACE gene was associated with development of diabetic nephropathy. D allele was more frequency among DN patients. Compared with the group of II genotype, the corresponding OR with 95% CI of the groups of ID genotype and DD genotype were 2.419( 1.180~4.959)and 3.417 (1.608~7.260) respectively. After adjusting for diabetic family history and history of hypertension, the results still showed that the association between ACE genotype and DN was statistically significant. Results from univariate conditional logistic regression analysis also showed that DN was associated with education level, diabetes duration, glycemia control, diabetic family history, history of hypertension, hypertension treatment, legume intake, serum creatinine level and serum level of high density lipoprotein (HDL) cholesterol. The corresponding OR with 95% CI were 0.400(0.176-0.908), 1.907(1.399-2.601), 1.553(1.033-2.337), 2.000(1.097-3.644), 2.055(1.170-3.610), 1.540(1.123-2.111), 1.359 (1.010-1.828), 4.000(1.927-8.304) and 0.390(0.164-0.924) respectively. However, after adjusting for possible confounding factors, the associations between these factors, including education level, glycemia control, hypertension treatment and serum HDL cholesterol level, and DN were statistically significant. No associations were observed between the following factors and DN, which were family history of hypertension, family history of coronary heart disease, exercise, smoking, alcohol drinking, tea drinking, meat intake, egg intake, milk intake, fat intake, vegetable intake, sweetmeat intake, times of pregnancy, the history of delivering macrosomia, character, body index, serum total cholesterol, triglycerides, low density lipoprotein and very low density lipoprotein cholesterol levels. ACE genotype and diabetes duration were found to have an interaction(OR=1.741, 95%CI:1.107 -2.740). When subjected to multivariate conditional logistic regression analysis, four factors remained statistical
associations with DN, which were ACE genotype(OR=1.890, 95%CI:1.146~ 3.118), diabetes duration(OR=2.302, 95%CI:1.507 ~ 3.515), legume intake (OR=1.629, 95%CI:1.054~ 2.519) and serum creatinine level (OR=5.918, 95%CI:2.224~ 15.750). No association was observed between I/D polymorphism of ACE gene and DN stage.
Conclusion: D allele of ACE gene was an independent predictive factor for diabetic nephropathy, long diabetes duration, increased legume intake and high serum creatinine level were associated with higher risk for the development of diabetic nephropathy.
引文
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48. William F. Keane, Barry M. Brenner, Dick De Zeeuw, et al. The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: The RENAAL Study. Kidney International, 2003,63: 1499-1507.
49. Stratton IM, Adler AI, Andrew H, et al. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS35): prospective observational study. BMJ, 2000; 321: 405-412.
50. Romano Nosadini. Blood glucose in relation to blood pressure control as risk factors in the progression of renal damage in type 2 diabetes. International Congress Series. 2000, 1253: 295～299
51．侯旭宏，王建华，冯凭．Ⅱ型糖尿病血糖控制情况与合并肾病的关系．中华流行病学杂志，2000；4(21)：263-265
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55．王文娟，王克安．第四章糖尿病流行病学进展．见李立明主编．流行病学进展(第10卷)．北京：北京医科大学出版社，2002：64-89
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57. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type
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59．罗敏，贾秀娟．糖尿病肾病的抗高血压治疗．基础医学与临床．2003；23(4)：263-265
60. Hideki Asakawa, Katsuto Tokunaga, Fusao Kawakami. Elevation of fibrinogen and thrombin-antithrombin Ⅲ complex levels of type 2 diabetes mellitus patients with retinopathy and nephropathy. Journal of Diabetes and Its Complications. 2000, 14: 121-126
61. C.E. Tan, L. S. Chew, L.F. Chio, et al.Cardiovascular risk factors and LDL subfraction profile in Type 2 diabetes mellitus subjects with good glycaemic control. Diabetes Research and Clinical Practice. 2001, 51: 107-114
62．张志将．糖尿病慢性并发症的危险因素．中国公共卫生，2001，17(11)：1004～1005
63．田凤华．中国糖尿病现状及初步分析．中华流行病学杂志，1998，19(6)：361-362
64．王建华，杨新军，孟庆和等．蔬菜摄入与2型糖尿病及其并发脑梗塞、心肌梗死、肾病的关系．中国慢性病预防与控制，2002；10(3)：100-101
65．陈玉，周玲，徐耀初等。2型糖尿病与遗传和环境关系相互关系的研究。中华预防医学杂志，2002；36(3)191-194
66. Liang-Yi Wu, Chi-Chang Juan, Low-Tong Ho, et al. Effect of Green Tea Supplementation on insulin sensitivity in Sprague-Dawley Rat. Journal of Agricultural and Chemistry, PAGE EST: 5.4
67．柳青，王秀问．糖尿病肾病的遗传问题．国外医学内分泌分册，1995；5(3)：149-150，167
68．张志将、吴元民、江萍等．社区人群中糖尿病并发症危险因素的探索研究．中国全科卫生，2001；12(4)：972-972
69．李建，韩文群，马傅玲．糖尿病患者营养知识和健康需求的相关分析．现代
预防医学，2002；29(5)：634-635
70．李红兵、武宝玉、袁申元．糖代谢异常者541例尿蛋白5年随访分析．首都医科大学学报，20031 24(1)：44-46
71．穆世惠，毕建军，白薇．2型糖尿病的病理对照研究．现代预防医学，2001；28(1)：36-37
72. José Francisco Téllez-Zenteno, Mario H. Cardiel. Risk factors association with Depression in patients with type 2 diabetes mellitus. Archives of Medical Research. 2002,33: 53～60
73．侯旭宏．2型糖尿病并发肾病危险因素研究。硕士学位论文，1999，5
74．陈肾仁，林丹，蔡应木等。糖尿病肾病患者血清血管紧张素转换酶与尿白蛋白排泄率的相关研究。临床内科杂志。1998，15(6)：312-314
75．邓先金，增学丰，卿光兰。血管紧张素转换酶抑制剂与血管紧张素Ⅱ-1型受体拮抗剂联用治疗早期糖尿病肾病。临床荟萃。2003，18(13)：721-723