正常T细胞表达和分泌的活性调节蛋白基因多态性与2型糖尿病肾病的关联性研究
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摘要
目的:炎症反应参与了糖尿病肾病的发生与发展,正常T细胞表达和分泌的活性调节蛋白(RANTES)属于C-C亚族趋化因子,肾小球系膜细胞及肾小管上皮细胞均可分泌RANTES,参与肾小球的硬化和肾间质的纤维化。有研究发现,RANTES启动子—403G/A基因多态性增加了RANTES基因表达水平,本研究旨在观察天津市汉族人RANTES启动子—403G/A基因多态性的分布情况,并探讨基因分布与2型糖尿病肾病的关联性。
方法:病例组(2型糖尿病组)244例,来自代谢病医院住院患者,根据尿白蛋白排泄率(UAER)分为三组,分别为正常白蛋白尿组(DNO组,共86例,男性34例,女性52例,年龄61.53±8.95)、微量白蛋白尿组(DN1组,共84例,男性44例,女性40例,年龄61.85±10.71)和临床白蛋白尿组(DN2组,共74例,男性40例,女性34例,年龄63.35±10.07)。对照组90例(男性38例,女性52例,年龄58.36±8.26),取自代谢病医院健康查体人群。收集临床资料,空腹取静脉血,以常规蛋白酶K快速裂解法提取外周血基因组DNA,应用聚合酶链反应—限制片断长度多态性(PCR-RFLP)法测定RANTES启动子—403G/A基因多态性。最后,对临床资料进行统计分析。
结果:(1) 各组基因分布均符合Hardy-Weinberg遗传平衡定律。(2) 在2型糖尿病组和对照组中均检测到RANTES启动子—403G/A基因多态性标记,存在G/G、G/A、A/A三种基因型和G、A两种等位基因。2型糖尿病组G/G、G/A、A/A三种基因型频率及A等位基因频率分别为50.4%、35.7%、13.9%及31.8%,对照组为41.1%、45.6%、13.3%及36.1%,两组间基因型频率及等位基因频率均无显著性差别(P>0.05)。(3) 正常白蛋白尿组、微量白蛋白尿组及临床白蛋白尿组G/G、G/A、A/A三种基因型频率及A等位基因频率分布分别为,DNO组59.3%、26.7%、14.0%及27.3%,DN1组53.6%、
Objectives: Inflammation reactions are associated with the occurrence and development of diabetic nephropathy. Regulated upon activation normal T cell expressed and secreted(RANTES), belonged to C-C subtribe chemokine , can be secreted by both mesangial cell of renal glomerulus and epithelial cells of renal tubule. RANTES is associated with the sclerosis of renal glomerulus and the f ibrosis of renal tubule interstitial. As showed recently,the single nucleotide polymorphism (SNP) in RANTES promoter -403G/A has an increase of RANTES gene expression. It is the aim of this study to investigate the distribution of the single nucleotide polymorphism in RANTES promoter —403G/A in the Han population in Tianjin, and to assess if it is possible that the distribution is associated with diabetic nephropathy in type 2 diabetes mellitus.Method: A total of 244 Han people was involved in the patients group(type 2 diabetes mellitus group) who are selected from the inpatients in Metabolism Disease Hospital, Tianjin Medical University. According to urine albumin excretion rate(UAER), it was classified into three groups, the normoalbuminuria group(DNO group, 86 people,34 male and 52 female, average age was 61.53 ± 8. 95), the microalbuminuria group(DNl group, 84 people, 44 male and 40 female, average age was 61. 85 ±10. 71), and the macroalbuminuria group(DN2 group, 74 people, 40 male
and 34 female, average age was 63. 35+10. 07). A total of 90 Han subjects was involved in the control group (38 male and 52 female, average age was 58.36 + 8.26). Clinical data was collected, and genomic DNA was extracted from peripheral blood cells using a Protease K Fasting Burst Technique. PCR-RFLP analysis was performed to screen the single nucleotide polymorphism in RANTES promoter — 403G/A. Finally, statistics anylysis was performed.Result: (1) The prevalence of the RANTES promoter - 403G/A genotypes and alleles in each group were consistent with Hardy-Weinberg equilibrium law. (2)A polymorphism of RANTES promoter —403G/A were screened both in the diabetes group and the control group. G/G> G/A and A/A genotypes and G^ A alleles were found. The frequency of the genotype and allele in the diabetes group was 50.4% for G/G, 35.7% for G/A, 13.9% for A/A genotype, and 31.8% for A allele. It was 41. 1%, 45. 6%, 13. 3% and 36.1% respectively in the control group. There was no significant difference between the two groups for the respective frequency of the genotypes and alleles(P>0. 05). (3) The frequency of the genotype and allele in the DNO was 59.3% for G/G, 26.7% for G/A, 14.0% for A/A genotype, and 27.3% for A allele. It was 53. 6%, 35. 7%, 10. 7% and 28.6% respectively in the DNl;And was 36. 5%, 45. 9%, 17. 6% and 40.5% respectively in the DN2. There was significant difference between the three groups for the respective frequency of the genotype and allele(P<0. 05). Followed by x2 division method, there was no significant difference between the DNO and DNl(P>0. 05). Merging the DNO and DN1 compared with the DN2 in result that significant difference were found between DN2 and DN0+DN1. A (+) genotype and A allele frequency in DN2 were higher than
方法:病例组(2型糖尿病组)244例,来自代谢病医院住院患者,根据尿白蛋白排泄率(UAER)分为三组,分别为正常白蛋白尿组(DNO组,共86例,男性34例,女性52例,年龄61.53±8.95)、微量白蛋白尿组(DN1组,共84例,男性44例,女性40例,年龄61.85±10.71)和临床白蛋白尿组(DN2组,共74例,男性40例,女性34例,年龄63.35±10.07)。对照组90例(男性38例,女性52例,年龄58.36±8.26),取自代谢病医院健康查体人群。收集临床资料,空腹取静脉血,以常规蛋白酶K快速裂解法提取外周血基因组DNA,应用聚合酶链反应—限制片断长度多态性(PCR-RFLP)法测定RANTES启动子—403G/A基因多态性。最后,对临床资料进行统计分析。
结果:(1) 各组基因分布均符合Hardy-Weinberg遗传平衡定律。(2) 在2型糖尿病组和对照组中均检测到RANTES启动子—403G/A基因多态性标记,存在G/G、G/A、A/A三种基因型和G、A两种等位基因。2型糖尿病组G/G、G/A、A/A三种基因型频率及A等位基因频率分别为50.4%、35.7%、13.9%及31.8%,对照组为41.1%、45.6%、13.3%及36.1%,两组间基因型频率及等位基因频率均无显著性差别(P>0.05)。(3) 正常白蛋白尿组、微量白蛋白尿组及临床白蛋白尿组G/G、G/A、A/A三种基因型频率及A等位基因频率分布分别为,DNO组59.3%、26.7%、14.0%及27.3%,DN1组53.6%、
Objectives: Inflammation reactions are associated with the occurrence and development of diabetic nephropathy. Regulated upon activation normal T cell expressed and secreted(RANTES), belonged to C-C subtribe chemokine , can be secreted by both mesangial cell of renal glomerulus and epithelial cells of renal tubule. RANTES is associated with the sclerosis of renal glomerulus and the f ibrosis of renal tubule interstitial. As showed recently,the single nucleotide polymorphism (SNP) in RANTES promoter -403G/A has an increase of RANTES gene expression. It is the aim of this study to investigate the distribution of the single nucleotide polymorphism in RANTES promoter —403G/A in the Han population in Tianjin, and to assess if it is possible that the distribution is associated with diabetic nephropathy in type 2 diabetes mellitus.Method: A total of 244 Han people was involved in the patients group(type 2 diabetes mellitus group) who are selected from the inpatients in Metabolism Disease Hospital, Tianjin Medical University. According to urine albumin excretion rate(UAER), it was classified into three groups, the normoalbuminuria group(DNO group, 86 people,34 male and 52 female, average age was 61.53 ± 8. 95), the microalbuminuria group(DNl group, 84 people, 44 male and 40 female, average age was 61. 85 ±10. 71), and the macroalbuminuria group(DN2 group, 74 people, 40 male
and 34 female, average age was 63. 35+10. 07). A total of 90 Han subjects was involved in the control group (38 male and 52 female, average age was 58.36 + 8.26). Clinical data was collected, and genomic DNA was extracted from peripheral blood cells using a Protease K Fasting Burst Technique. PCR-RFLP analysis was performed to screen the single nucleotide polymorphism in RANTES promoter — 403G/A. Finally, statistics anylysis was performed.Result: (1) The prevalence of the RANTES promoter - 403G/A genotypes and alleles in each group were consistent with Hardy-Weinberg equilibrium law. (2)A polymorphism of RANTES promoter —403G/A were screened both in the diabetes group and the control group. G/G> G/A and A/A genotypes and G^ A alleles were found. The frequency of the genotype and allele in the diabetes group was 50.4% for G/G, 35.7% for G/A, 13.9% for A/A genotype, and 31.8% for A allele. It was 41. 1%, 45. 6%, 13. 3% and 36.1% respectively in the control group. There was no significant difference between the two groups for the respective frequency of the genotypes and alleles(P>0. 05). (3) The frequency of the genotype and allele in the DNO was 59.3% for G/G, 26.7% for G/A, 14.0% for A/A genotype, and 27.3% for A allele. It was 53. 6%, 35. 7%, 10. 7% and 28.6% respectively in the DNl;And was 36. 5%, 45. 9%, 17. 6% and 40.5% respectively in the DN2. There was significant difference between the three groups for the respective frequency of the genotype and allele(P<0. 05). Followed by x2 division method, there was no significant difference between the DNO and DNl(P>0. 05). Merging the DNO and DN1 compared with the DN2 in result that significant difference were found between DN2 and DN0+DN1. A (+) genotype and A allele frequency in DN2 were higher than
引文
[1] 廖二原,超楚生.内分泌学(下册)[M].第一版.北京:人民卫生出版社,2001.1434.
[2] 茅彩萍,顾振纶.糖尿病肾病发病机制的研究进展[J].中国血液流变学杂志,2002,12(2):148-152.
[3] Ayodele OE, Alebiosu CO, Salako BL. Diabetic nephropathy—a review of the natural history, burden, risk factors and treatment[J]. J Natl Med Assoc, 2004, 96(11): 1445-1454.
[4] American Diabetes Association[J]. Diabetic Nephropathy. Diabetes Care, 2003, 26: S94-S98.
[5] 李秀钧,邬云红.糖尿病是一种炎症性疾病[J]?中华内分泌代谢杂志,2003,19(4):251-253.
[6] Moriwaki Y, Yamamoto T, Shibutani Y, et al. Elevated levels of interleukin-18 and tumor necrosis factor-alpha in serum of patients with type 2 diabetes mellitus: relationship with diabetic nephropathy[J]. Metabolism, 2003, 52(5): 605-608.
[7] Sassy-Prigent C, Heudes D, Mandet C, et al. Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats[J]. Diabetes, 2000, 49(3): 466-475.
[8] Chow F, Ozols E, Nikolic-Paterson DJ, et al. Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury[J]. Kidney Int, 2004, 65(1): 116-128.
[9] Wang SN, LaPage J, Hirschberg R. Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy[J]. Kidney Int, 2000, 57(3): 1002-1014.
[10] Hajeer AH, al Sharif F, Ollier WE. A polymorphism at position -403 in the human RANTES promoter[J]. Eur J Immunogenet, 1999, 26(5): 375-376.
[11] al Sharif F, Oilier WE, Hajeer AH. A rare polymorphism at position-28 in the human RANTES promoter[J]. Eur J Immunogenet, 1999, 26(5): 373-374.
[12] Hizawa N, Yamaguchi E, Konno S, et al. A functional polymorphism in the RANTES gene promoter is associated with the development of late-onset asthma[J]. Am J Respir Crit Care Med, 2002, 166(5): 686-690.
[13] Nakajima K, Tanaka Y, Nomiyama T, et al. RANTES promoter genotype is associated with diabetic nephropathy in type 2 diabetic subjects[J]. Diabetes Care, 2003, 26(3): 892-898.
[14] 高爱宝,肖剑,吴登俊.SNPs基因分型技术[J].生物技术,2004,14(3):63—65.
[15] 杨仕贵,叶冬青.安徽省汉族SLE患者和正常人RANTES单核苷酸多态性及CCR5基因多态性的比较[J].中华微生物和免疫学杂志,2003,23(9):723—727.
[16] Yao TC, Kuo ML, See LC, et al. The RANTES promoter polymorphism: A genetic risk factor for near-fatal asthma in Chinese children[J]. J Allergy Clin Immunol, 2003, 111: 1285-1292.
[17] Appay V, Brown A, Cribbes S, et al. Aggregation of RANTES is responsible for its inflammatory properties. Characterization of nonaggregating, noninflammatory RANTES mutants[J]. J Biol Chem, 1999, 274(39): 27505-27512.
[18] Wong M, Uddin S, Majchrzak B, et al. Rantes activates Jak2 and Jak3 to regulate engagement of multiple signaling pathways in T cells[J]. J Biol Chem, 2001, 276(14): 11427-11431.
[19] Locati M, Deuschle U, Massardi ML, et al. Analysis of the gene expression profile activated by the CC chemokine ligand 5/RANTES and by lipopolysaccharide in human monocytes[J]. J Immunol, 2002, 168(7): 3557-3562.
[20] Luster A D. Chemokines-Chemotactic cytokines that mediateinflammation. N Engl J Med, 1998, 338: 436-445.
[21] Kim JJ, Lee JH, Jang CH, et al. Chemokine RANTES promoter polymorphisms in allergic rhinitis[J]. Laryngoscope, 2004, 114(4): 666 -669.
[22] Nakajima K, Tanaka Y, Nomiyama T, et al. Chemokine receptor genotype is associated with diabetic nephropathy in Japanese with type 2 diabetes[J]. Diabetes, 2002, 51(1): 238-242.
[23] McDermott DH, Beecroft MJ, Kleeberger CA, et al. Chemokine RANTES promoter polymorphism affects risk of both HIV infection and disease progression in the Multicenter AIDS Cohort Study[J]. AIDS, 2000, 14(17): 2671-2678.
[24] 刘雪林,王福生,金磊等.汉族人群RANTES基因多态性与艾滋病病毒1感染关系的初步研究[J].中华流行病学杂志,2003,24(11):975-975.
[25] Gomes MB, Nogueira VG. Acute-phase proteins and microalbuminuria among patients with type 2 diabetes[J]. Diabetes Res Clin Pract, 2004, 66(1): 31-39.
[26] Shikano M, Sobajima H, Yoshikawa H, et al. Usefulness of a highly sensitive urinary and serum IL-6 assay in patients with diabetic nephropathy[J]. Nephron, 2000, 85(1): 81-85.
[27] Roestenberg P, van Nieuwenhoven FA, Wieten L, et al. Connective tissue growth factor is increased in plasma of type 1 diabetic Patients with nephropathy [J]. Diabetes Care, 2004, 27 (5) : 1164-1170.
[28] 黄文辉,倪安民.单核细胞趋化蛋白—1、正常T细胞活化表达和分泌调节蛋白与2型糖尿病肾病患者肾小管间质损害的关系研究[J].临床荟萃,2004,19(7):365-368.
[29] Morii T, Fujita H, Narita T, et al. Increased urinary excretion of monocyte chemoattractant protein-1 in proteinuric renal diseases[J]. Ren Faii, 2003, 25(3): 439-444.
[30] Koshimura J, Fujita H, Narita T, et al. Urinary adiponectin excretion is increased in patients with overt diabetic nephropathy[J]. Biochem Biophys Res Commun, 2004, 316(1): 165-169.
[31] Mezzano S, Aros C, Droguett A, et al. NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy[J]. Nephrol Dial Transplant, 2004, 19(10): 2505-2512.
[32] Chow FY, Nikolic-Paterson DJ, Atkins RC, et al. Macrophages in streptozotocin-induced diabetic nephropathy: potential role in renal fibrosis[J]. Nephrol Dial Transplant, 2004, 19(12): 2987-2896.
[33] Furuta T, Saito T, Ootaka T, et al. The role of macrophages in diabetic glomerulosclerosis[J]. Am J Kidney Dis, 1993, 21(5): 480-485.
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[44] von Hundelshausen P, Weber KS, Huo Y, et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium[J]. Circulation, 2001, 103(13): 1772-1777.
[2] 茅彩萍,顾振纶.糖尿病肾病发病机制的研究进展[J].中国血液流变学杂志,2002,12(2):148-152.
[3] Ayodele OE, Alebiosu CO, Salako BL. Diabetic nephropathy—a review of the natural history, burden, risk factors and treatment[J]. J Natl Med Assoc, 2004, 96(11): 1445-1454.
[4] American Diabetes Association[J]. Diabetic Nephropathy. Diabetes Care, 2003, 26: S94-S98.
[5] 李秀钧,邬云红.糖尿病是一种炎症性疾病[J]?中华内分泌代谢杂志,2003,19(4):251-253.
[6] Moriwaki Y, Yamamoto T, Shibutani Y, et al. Elevated levels of interleukin-18 and tumor necrosis factor-alpha in serum of patients with type 2 diabetes mellitus: relationship with diabetic nephropathy[J]. Metabolism, 2003, 52(5): 605-608.
[7] Sassy-Prigent C, Heudes D, Mandet C, et al. Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats[J]. Diabetes, 2000, 49(3): 466-475.
[8] Chow F, Ozols E, Nikolic-Paterson DJ, et al. Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury[J]. Kidney Int, 2004, 65(1): 116-128.
[9] Wang SN, LaPage J, Hirschberg R. Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy[J]. Kidney Int, 2000, 57(3): 1002-1014.
[10] Hajeer AH, al Sharif F, Ollier WE. A polymorphism at position -403 in the human RANTES promoter[J]. Eur J Immunogenet, 1999, 26(5): 375-376.
[11] al Sharif F, Oilier WE, Hajeer AH. A rare polymorphism at position-28 in the human RANTES promoter[J]. Eur J Immunogenet, 1999, 26(5): 373-374.
[12] Hizawa N, Yamaguchi E, Konno S, et al. A functional polymorphism in the RANTES gene promoter is associated with the development of late-onset asthma[J]. Am J Respir Crit Care Med, 2002, 166(5): 686-690.
[13] Nakajima K, Tanaka Y, Nomiyama T, et al. RANTES promoter genotype is associated with diabetic nephropathy in type 2 diabetic subjects[J]. Diabetes Care, 2003, 26(3): 892-898.
[14] 高爱宝,肖剑,吴登俊.SNPs基因分型技术[J].生物技术,2004,14(3):63—65.
[15] 杨仕贵,叶冬青.安徽省汉族SLE患者和正常人RANTES单核苷酸多态性及CCR5基因多态性的比较[J].中华微生物和免疫学杂志,2003,23(9):723—727.
[16] Yao TC, Kuo ML, See LC, et al. The RANTES promoter polymorphism: A genetic risk factor for near-fatal asthma in Chinese children[J]. J Allergy Clin Immunol, 2003, 111: 1285-1292.
[17] Appay V, Brown A, Cribbes S, et al. Aggregation of RANTES is responsible for its inflammatory properties. Characterization of nonaggregating, noninflammatory RANTES mutants[J]. J Biol Chem, 1999, 274(39): 27505-27512.
[18] Wong M, Uddin S, Majchrzak B, et al. Rantes activates Jak2 and Jak3 to regulate engagement of multiple signaling pathways in T cells[J]. J Biol Chem, 2001, 276(14): 11427-11431.
[19] Locati M, Deuschle U, Massardi ML, et al. Analysis of the gene expression profile activated by the CC chemokine ligand 5/RANTES and by lipopolysaccharide in human monocytes[J]. J Immunol, 2002, 168(7): 3557-3562.
[20] Luster A D. Chemokines-Chemotactic cytokines that mediateinflammation. N Engl J Med, 1998, 338: 436-445.
[21] Kim JJ, Lee JH, Jang CH, et al. Chemokine RANTES promoter polymorphisms in allergic rhinitis[J]. Laryngoscope, 2004, 114(4): 666 -669.
[22] Nakajima K, Tanaka Y, Nomiyama T, et al. Chemokine receptor genotype is associated with diabetic nephropathy in Japanese with type 2 diabetes[J]. Diabetes, 2002, 51(1): 238-242.
[23] McDermott DH, Beecroft MJ, Kleeberger CA, et al. Chemokine RANTES promoter polymorphism affects risk of both HIV infection and disease progression in the Multicenter AIDS Cohort Study[J]. AIDS, 2000, 14(17): 2671-2678.
[24] 刘雪林,王福生,金磊等.汉族人群RANTES基因多态性与艾滋病病毒1感染关系的初步研究[J].中华流行病学杂志,2003,24(11):975-975.
[25] Gomes MB, Nogueira VG. Acute-phase proteins and microalbuminuria among patients with type 2 diabetes[J]. Diabetes Res Clin Pract, 2004, 66(1): 31-39.
[26] Shikano M, Sobajima H, Yoshikawa H, et al. Usefulness of a highly sensitive urinary and serum IL-6 assay in patients with diabetic nephropathy[J]. Nephron, 2000, 85(1): 81-85.
[27] Roestenberg P, van Nieuwenhoven FA, Wieten L, et al. Connective tissue growth factor is increased in plasma of type 1 diabetic Patients with nephropathy [J]. Diabetes Care, 2004, 27 (5) : 1164-1170.
[28] 黄文辉,倪安民.单核细胞趋化蛋白—1、正常T细胞活化表达和分泌调节蛋白与2型糖尿病肾病患者肾小管间质损害的关系研究[J].临床荟萃,2004,19(7):365-368.
[29] Morii T, Fujita H, Narita T, et al. Increased urinary excretion of monocyte chemoattractant protein-1 in proteinuric renal diseases[J]. Ren Faii, 2003, 25(3): 439-444.
[30] Koshimura J, Fujita H, Narita T, et al. Urinary adiponectin excretion is increased in patients with overt diabetic nephropathy[J]. Biochem Biophys Res Commun, 2004, 316(1): 165-169.
[31] Mezzano S, Aros C, Droguett A, et al. NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy[J]. Nephrol Dial Transplant, 2004, 19(10): 2505-2512.
[32] Chow FY, Nikolic-Paterson DJ, Atkins RC, et al. Macrophages in streptozotocin-induced diabetic nephropathy: potential role in renal fibrosis[J]. Nephrol Dial Transplant, 2004, 19(12): 2987-2896.
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