血管紧张素原基因M235T分子变异与2型糖尿病肾病的关系

目的　探讨血管紧张素原（ａｎｇｉｏｔｅｎｓｉｎｏｇｅｎ , Ａ Ｇ Ｔ） 基因 Ｍ２３５ Ｔ 分子变异与中国人无肾病并发症的２ 型糖尿病（ｄｉａｂｅｔｅｓ ｍ ｅｌｌｉｔｕｓ , Ｄ Ｍ） 、２ 型糖尿病肾病（ｄｉａｂｅｔｉｃ ｎｅｐｈｒｏｐａｔｈｙ , Ｄ Ｎ） 的关系。方法　用 Ｐ Ｃ Ｒ及 Ｒ Ｆ Ｌ Ｐ 方法对８４ 例 Ｄ Ｍ、９６ 例 Ｄ Ｎ 及９８ 名正常对照进行了 Ａ Ｇ Ｔ 基因 Ｍ２３５ Ｔ 多态性的检测。结果　 Ｄ Ｎ 组 Ｔ 等位基因频率０８２ , Ｔ Ｔ 基因型频率０７０ ,与对照组（０６３ ,０４３） 比较有显著差异（ Ｐ＝ ０００３ , Ｐ＝００００４） ;校正了 Ｄ Ｎ 的几种危险因素后, Ｔ Ｔ 基因型对 Ｄ Ｎ 的 Ｏ Ｒ 为３４７（９５ ％ Ｃ Ｉ 为１５１ ～７９４ , Ｐ＝０００３３） 。 Ｄ Ｍ 组基因型频率分布与对照组比较无显著差异（ Ｐ＞ ００５） 。结论　 Ａ Ｇ Ｔ 基因 Ｔ Ｔ 型可能是中国人群２ 型糖尿病肾病的独立危险因素之一。     

血管紧张素原基因M235T分子变异与心肌梗塞的关系

目的为探讨血管紧张素原（ＡＧＴ）基因Ｍ２３５Ｔ分子变异与心肌梗塞（ＭＩ）的关系。方法采用聚合酶链反应、限制性片段长度多态性分析，对５７例ＭＩ患者和７６例无冠心病证据的对照组进行ＡＧＴ基因Ｍ２３５Ｔ等位基因检测。结果ＭＩ患者ＡＧＴ基因２３５ＴＴ型（０．７０）和Ｔ２３５等位基因（０．８２）的频率显著高于对照组（分别为０．４２和０．６３，Ｐ＝０．０１３和Ｐ＜０．０２５）。经校正冠心病的主要危险因素后，ＡＧＴ基因２３５ＴＴ型仍可显著增加心肌梗塞发生的危险性（比数比３．６５，Ｐ＝０．０１６）。结论ＡＧＴ基因２３５ＴＴ型可能是中国人群ＭＩ发病的重要危险因素之一。     

血管紧张素原基因CD235Met→Thr变异与脑梗塞发病的关系

目的 探讨血管紧张素原（ａｎｇｉｏｔｅｎｓｉｎｏｇｅｎ,ＡＧＴ）ＡＤ ＬＤ ＥＴ→Ｔｈｒ变异与中国人脑梗塞发病的关系。方法 应用聚合酶链反应－限制笥片段长度多态性分析,对８２名正常健康人和１０２例脑梗塞患者进行了ＡＧＴ基因ＣＤ２３５Ｍｅｔ→Ｔｈｒ变异多态性分析。结果 经ｘ＾２检验,ＡＧＴ基因Ｔ／Ｔ基因型和Ｔ等位基因频率脑梗塞组（５１．９％和７０．１％）与正常对照组（４２．０％和６５．２％）之间相比     

利用特异性寡核苷酸探针检测非IgA系膜增殖性肾炎H…

本文报道利用多聚酶链反应（ＰＣＲ）技术及特异性寡核苷酸（ＳＳＯ）探针检测了１００例原发性非ＩｇＡ系膜增殖性肾炎（Ｎｏｎ－ＩｇＡ ＭｓＰＧＮ）患者ＨＬＡ－ＤＲ等位基因频率，并与２５５例中国北方汉族正常人进行了比较，发现ＨＬＡ－ＤＲ１２（５）等位基因频率在Ｎｏｎ－ＩｇＡ ＭｓＰＧＮ患者明显高于正常人（２７．０ｖｓ７．８，Ｐｃ＜０．０１）。并从免疫遗传学角度对ＨＬＡ车Ｎｏｎ－ＩｇＡ，ＭｓＰＧＮ的关联进行     

利用特异性寡核苷酸探针检测非IgA系膜增殖性肾炎HLA－DR基因频率

本文报道利用多聚酶链反应（ＰＣＲ）技术及特异性寡核苷酸（ＳＳＯ）探针检测了１００例原发性非ＩｇＡ系膜增殖性肾炎（Ｎｏｎ－ＩｇＡＭｓＰＧＮ）患者ＨＬＡ－ＤＲ等位基因频率，并与２５５例中国北方汉族正常人进行了比较，发现ＨＬＡ－ＤＲ１２（５）等位基因频率在Ｎｏｎ－ＩｇＡＭｓＰＧＮ患者明显高于正常人（２７．０ｖｓ７．８，Ｐｃ＜０．０１）。并从免疫遣传学角度对ＨＬＡ与Ｎｏｎ－ＩｇＡＭｓＰＧＮ的关联进行了探讨。     

I型糖尿病患者的HLA—DR—DQ基因单体型分析

应用ＨＬＡ－ＤＲＢ，ＤＱＢ１序列特异性引物ＰＣＲ扩增方法，鉴定８１例ＩＤＤＭ患者，７个家系和８４例正常对照汉族人群的ＤＲＢ基因多态性及ＩＤＤＭ的ＨＬＡ－ＤＲ－ＤＱ基因单体型。结果表明：（１）ＩＤＤＭ患者ＤＲＢ１＊０３，ＤＲＢ１＊０９等位基因频率明显高于对照组，其频率分别为８．６４％ｖ．ｓ３．０％和２８．４％ｖ．ｓ１６．１（Ｐ〈０．０５）。（２）患者中ＤＲＢ１－ＤＲＢ３／ＤＲＢ１－ＤＲＢ４基因型频率     

中国人2型糖尿病的基因分型和定位

目的　对中国人２ 型糖尿病即非胰岛素依赖型糖尿病（ＮＩＤＤＭ）家系基因组ＤＮＡ进行基因分型及基因定位。　方法　采用分布于１～２２ 号染色体及Ｘ染色体上的３５８ 对荧光标记的微卫星引物,进行多重ＰＣＲ,ＰＣＲ扩增产物用聚丙烯酰胺凝胶电泳（ＰＡＧＥ）分离,然后进行电泳图谱及信息收集。应用ＧｅｎｅｓｃａｎＴＭ ３．０ 软件和Ｇｅｎｏ－ｔｙｐｅＴＭ ２．１ 软件进行基因分型和基因定位。　结果　在３５ 个家系中共有１９３ 个微卫星标志能准确进行基因分型。共得４１ ４９５ 个基因型。经过多点连锁分析和患病同胞对分析,初步确定在１,１０,１２,１８,２０号染色体上存在ＮＩＤＤＭ 相关基因位点。　结论　用全基因组扫描技术可以对中国人２ 型糖尿病相关基因位点进行基因分型和基因定位。     

1型血管紧张素Ⅱ受体基因与中国人冠心病、高血压及糖尿病的关系

目的本研究旨在观察１型血管紧张素Ⅱ受体（ＡＧＴＲ１）基因与中国人冠心病（ＣＨＤ）、高血压（ＨＴＮ）及非胰岛素依赖型糖尿病（ＮＩＤＤＭ）的相关情况，并在相关疾病中观察ＡＧＴＲ１基因与血管紧张素Ⅰ转换酶（ＡＣＥ）基因在发病中的相互关系。方法以２７０例ＣＨＤ、ＨＴＮ及ＮＩＤＤＭ单一或不同组合的中国人为对象，用ＰＣＲ／ＤｄｅⅠ酶解检测位于ＡＧＴＲ１基因３′－ＵＴＲ的Ａ１１６６Ｃ变异，并用ＰＣＲ检测ＡＣＥ基因内含子１６的插入／缺失多态标记。结果（１）ＧＡＴＲ１基因与ＣＨＤ相关（１ｏｇｉｓｔｉｃ回归分析，Ｐ＝０．０２）而与ＨＴＮ及ＮＩＤＤＭ无相关；（２）ＡＧＴＲ１基因对ＣＨＤ的参与风险率为１２．４％，比数比４．５５。与ＡＣＥ基因同属ＣＨＤ的独立变异因素（分别为Ｐ＝０．０３２及Ｐ＝０．００２）；（３）ＡＧＴＲ１－Ａ１１６６Ｃ变异不是通过对体脂含量、血脂水平及血压的影响参与ＣＨＤ发病；（４）个体的ＡＧＴＲ１基因及ＡＣＥ基因的联合基因型分析见到ＣＨＤ者与对照者间频率分布有显著差异（Ｐ＝０．０００２）。结论ＡＧＴＲ１基因参与中国人ＣＨＤ发病，并是ＣＨＤ发病的独立风险因素。     

Ⅰ型糖尿病患者的HLA-DR-DQ基因单体型分析

应用ＨＬＡ－ＤＲＢ，ＤＱＢ１序列特异性引物ＰＣＲ扩增方法，鉴定８１例ＩＤＤＭ患者，７个家系和８４例正常对照汉族人群的ＤＲＢ基因多态性及ＩＤＤＭ的ＨＬＡ－ＤＲ－ＤＱ基因单体型。结果表明：（１）ＩＤＤＭ患者ＤＲＢ１＊０３，ＤＲＢ１＊０９等位基因频率明显高于对照组，其频率分别为８．６４％ｖ．ｓ３．０％和２８．４％ｖ．ｓ１６．１（Ｐ＜０．０５）。（２）患者中ＤＲＢ１－ＤＲＢ３／ＤＲＢ１－ＤＲＢ４基因型频率明显高于对照组，即１９．８％ｖ．ｓ６．７％（Ｐ＜０．０５）。（３）首次证明ＤＲＢ１＊１２等位基因与中国人ＩＤＤＭ正相关。上述结果提示不同种族ＨＬＡ－ＤＲ型别分布的差异，可能是不同种族人群ＩＤＤＭ发病率变化的分子基础。     

血管紧张素转换酶基因缺失纯合型与糖尿病肾病相关联

应用ＰＣＲ扩增方法检测２０３例ＮＩＤＤＭ患者和１６５例正常对照者血管紧张素（ＡＣＥ）基因的１６内含子中２８７ｂｐ片段缺失／插入多态性。结果显示,糖尿病肾病患者组ＡＣＥ基因缺失纯合型（ＤＤ）频率明显高于非肾病组和正常对照组,Ｐ〈０．００１;ＤＤ缺失纯合型患者肾病进展速度明显快于缺失／插入（ＤＩ）杂合型及插入／插入（ＩＩ）纯合型糖尿病患者,Ｐ〈０．０１。表明ＡＣＥ基因缺失纯合型是糖尿病肾病的独立危险因     

PPARγ2基因Pro12Ala多态性与DM2-N易患性的关系

目的:研究我国北方汉族人群PPARγ2基因Pro12Ala多态性与2型糖尿病肾病(DM2-N)易患性的关系.方法:应用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法检测了78例2型糖尿病(DM2)患者(糖尿病肾病组患者41例,非糖尿病肾病组患者37例)及38例正常对照组的PPARγ2基因Pro12Ala多...     

XbaI GLUT1 Gene Polymorphism and the Risk of Type 2 Diabetes with Nephropathy

Altered expression of the facilitated glucose transporter GLUT1 affects pathways implicated in the pathogenesis of diabetic nephropathy. There is indication that variation of GLUT1 gene (SLC2A1) contributes to development of microangiopathy in diabetes mellitus type 2 (DM) patients. A genetic association study involving Caucasians was carried out to investigate the role of XbαI polymorphism in the GLUT1 gene in diabetic nephropathy (DN). Study population (n = 240) consisted of 148 unrelated patients with DM (92 cases with diabetic nephropathy (DN)), and of 92 matched healthy control subjects. Diabetic nephropathy was defined as persistent albuminuria (> 300 mg/24 h) and/or renal failure, in the absence of non-diabetes induced renal disease. The analysis showed that the risk of developing DM and DN in XbaI(−) carriers, when healthy individuals were considered as controls, was two-fold: odds ratio (OR) 2.08 [95% confidence interval (1.14–3.79)]. However, there was no evidence of association between XbaI(−) and DN when patients with DM and without DN were considered as controls: OR = 1.12 (0.55–2.26). Thus, the GLUT1 XbaI(−) allele is associated with DM, and possibly with a more severe form of the disease that can lead to development of DN.     

Interleukin-1β Gene (IL1B) Polymorphism and Risk of Developing Diabetic Nephropathy

Objective: Cytokines play an important role in the pathogenesis of type 2 diabetes (T2DM) and its complications. The aim of the study was to evaluate an association of the ?511 (C/T) polymorphism in the IL1B gene with diabetic nephropathy (DN).

Methods: The study population included 860 patients with T2DM (506 with diabetic nephropathy and 354 without nephropathy) as well as 505 healthy individuals. Genomic DNA was genotyped for the IL1B ?511 (C/T) polymorphism using PCR-RFLP technique.

Results: The IL1B ?511 C/T polymorphism was genotyped in 860 T2DM patients with or without DN and 505 healthy individuals. The average age of patients was 65.3 years in DN+ and 62.2 years in DN- subgroups. The genotype distribution did not differ significantly between patients and controls. Only a tendency to a slight increase of T allele frequency was observed in patient group. Genotype and allele frequencies of ?511 C/T polymorphism were compared in patients with DN and those without it. The minor allele (T) and homozygote TT frequencies were significantly different between subgroups. The T allele was more frequent in DN+ patients, with odds ratio 1.45 (95% CI 1.2–1.8), p = 0.0003. The TT genotype frequency was also higher in DN+, with OR 1.76 (96% CI 1.1–2.7), p = 0.01.

Conclusion: In a studied population the ?511 C/T polymorphism in the IL1B gene is associated with diabetic nephropathy in dialyzed T2DM patients. Further studies are required to confirm the clinical significance of this finding.     

肾素-血管紧张素系统基因多态性与糖尿病及合并肾病的关系

目的探讨血管紧张素I转换酶(ACE)基因及血管紧张素原(AGT)基因与2型糖尿病(DM)及合并糖尿病肾病(DN)的相关性。方法分别用PCR、突变基因分离聚合酶链反应(MS-PCR)技术对195例2型DM患者和136例正常对照者的ACEI/D与AGTM235T多态性进行检测。结果(1)DM组ACE-DD基因型和D等位基因频率均比对照组显著增高(P<0.001)。(2)DN(+)组ACE基因型和等位基因频率与DN(-)组比较无显著性差异。(3)AGT基因型分布与等位基因频率在3组中均无显著性差异。(4)联合分析ACE-DD型及AGT-TT型对DN(+)、DN(-)的OR分别为4.17和3.16;均高于单基因DD型及TT型的OR值。结论(1)ACEDD基因型和D等位基因可能是广西地区人群2型DM的易感因素。(2)未发现ACEI/D或AGTM235T多态性单一因素与2型DM患者中DN的发生有关联。(3)ACE-DD基因型与AGTM235T-TT基因型在2型DM及DN发生中有协同作用。     

Association of polymorphisms in monocyte chemoattractant protein-1 promoter with diabetic kidney failure in Korean patients with type 2 diabetes mellitus

Monocyte chemoattractant protein-1 (MCP-1) is suggested to be involved in the progression of diabetic nephropathy. We investigated the association of the -2518 A/G polymorphism in the MCP-1 gene with progressive kidney failure in Korean patients with type 2 diabetes mellitus (DM). We investigated -2518 A/G polymorphism of the MCP-1 gene in type 2 DM patients with progressive kidney failure (n=112) compared with matched type 2 DM patients without nephropathy (diabetic control, n=112) and healthy controls (n=230). The overall genotypic distribution of -2518 A/G in the MCP-1 gene was not different in patients with type 2 DM compared to healthy controls. Although the genotype was not significantly different between the patients with kidney failure and the diabetic control (p=0.07), the A allele was more frequent in patients with kidney failure than in DM controls (42.0 vs. 32.1%, p=0.03). The carriage of A allele was significantly associated with kidney failure (68.8 vs. 54.5%, OR 1.84, 95% CI 1.07-3.18). In logistic regression analysis, carriage of A allele retained a significant association with diabetic kidney failure. Our result shows that the -2518 A allele of the MCP-1 gene is associated with kidney failure in Korean patients with type 2 DM.     

血管紧张素原基因M235T多态性与肥厚型心肌病的关系

目的　探讨血管紧张素原 ( angiotensinogen,AGT)基因 M2 35 T变异与肥厚型心肌病( hypertrophic cardiomyopathy,HCM)的关系。方法　对 72例 HCM患者与 80名正常对照者进行病例 -对照研究。采用聚合酶链反应与限制性片段长度多态性技术检测 AGT基因 M2 35 T变异。同时通过 M型二维超声心动图分别测量室间隔、左室后壁和心尖部心肌厚度。结果　 ( 1)经 PCR扩增及 Tth111 酶切 ,AGT基因型有 3种形式 :MM、TT与 MT基因型。两组 AGT基因型的分布均符合 Hardy- Weinberg平衡。 ( 2 )AGT基因 M2 35 T基因型在 HCM组与对照组的分布差异有显著性 ( χ2 =6 .0 90 ,P<0 .0 5 )。HCM组 TT基因型与 T2 35等位基因的频率均高于对照组 ( TT基因型 :0 .6 3vs0 .4 5 ,OR=2 .0 37,95 % CI:1.0 6 4～7.899,P<0 .0 5 ;T2 35等位基因 :0 .78vs0 .6 4 ,OR=1.990 ,95 % CI:1.197～ 3.30 8,P<0 .0 1)。 ( 3) HCM组TT基因型患者左室壁最厚处平均厚度明显大于 MM、MT基因型患者 [( 19.1± 4 .8) mm vs( 15 .3± 2 .6 )mm与 ( 16 .2± 5 .1) mm,F=4 .2 6 1,P<0 .0 5 ]。结论　 AGT基因 M2 35 T变异与 HCM的发病显著相关 ,TT基因型或 T2 35等位基因可能是参与 HCM发生及加重心肌肥厚的一个遗传方面的危险因素     

Association of rs11643718 SLC12A3 and rs741301 ELMO1 Variants with Diabetic Nephropathy in South Indian Population

This study reports on the association of genetic variants selected from previous genome‐wide association studies for type 2 diabetic nephropathy in south Indians. Eight variants were genotyped in 601 type 2 diabetic subjects without nephropathy (DM) and 583 type 2 diabetic subjects with nephropathy (DN) by MassARRAY. The minor allele frequencies of rs11643718 SLC12A3 variant and rs741301 ELMO1 variant were significantly different between DM and DN groups (P = 0.029 and 0.016, respectively). A combined analysis showed that the subjects carrying the risk genotypes of both these variants (GG of rs11643718 + AG/AA of rs741301) had a significant association with DN with an odds ratio [adjusted for age, sex, Body Mass Index (BMI), HbA1c, and systolic Blood Pressure (BP)] of 1.73 (1.30–2.30, P = 1.72 × 10^–4) as compared to subjects carrying all other genotype combinations. This is the first study to report a significant association of the SLC12A3 rs11643718 and ELMO1 rs741301 (Single nucleotide Polymorphism) SNPs with diabetic nephropathy in south Indians.     

Aberrant activation profile of cytokines and mitogen-activated protein kinases in type 2 diabetic patients with nephropathy

Cytokine-induced inflammation is involved in the pathogenesis of type 2 diabetes mellitus (DM). We investigated plasma concentrations and ex vivo production of cytokines and chemokines, and intracellular signalling molecules, mitogen-activated protein kinases (MAPK) in T helper (Th) cells and monocytes in 94 type 2 diabetic patients with or without nephropathy and 20 healthy controls. Plasma concentrations of inflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-18 and chemokine CCL2 in patients with diabetic nephropathy (DN) were significantly higher than control subjects, while IL-10, CXCL8, CXCL9, CXCL10 and adiponectin concentrations of DN were significantly higher than patients without diabetic nephropathy (NDN) and control subjects (all P < 0.05). Plasma concentrations of TNF-alpha, IL-6, IL-10, IL-18, CCL2, CXCL8, CXCL9, CXCL10 and adiponectin exhibited significant positive correlation with urine albumin : creatinine ratio in DN patients. The percentage increases of ex vivo production of IL-6, CXCL8, CXCL10, CCL2 and CCL5 upon TNF-alpha activation were significantly higher in both NDN and DN patients than controls (all P < 0.05). The percentage increases in IL-18-induced phosphorylation of extracellular signal-regulated kinase (ERK) in Th cells of NDN and DN were significantly higher than controls (P < 0.05), while the percentage increase in TNF-alpha-induced phosphorylation of p38 MAPK in monocytes and IL-18-induced phosphorylation of p38 MAPK in Th cells and monocytes were significantly higher in NDN patients than controls. These results confirmed that the aberrant production of inflammatory cytokines and chemokines and differential activation of MAPK in different leucocytes are the underlying immunopathological mechanisms of type 2 DM patients with DN.