ACE基因、AT1R基因多态性与2型糖尿病肾病的关系

目的研究血管紧张素I转化酶(ACE)基因/D多态及血管紧张素受体1型(AT1R)A1166C多态性与中国汉族人2型糖尿病肾病(DN)的关系。方法运用聚合酶链反应(PCR)和PCR/DdeI酶切技术,检测93例DN患者(DN组)与94例2型糖尿病患者(DM组)ACE基因及AT1R基因多态基因型。结果DN组ACE基因DD基因型频率(34.4%)、D型等位基因频率(54.3%)较DM组(19.1%,40.4%)均升高(P<0.05,<0.01);两组间AT1R基因A1166C多态基因型频率和等位基因频率分布均无差异(P>0.05);ACE和AT1R基因多态与DN的分层分析显示,同时携带ACE纯合子缺失基因型(DD)和AT1R突变基因型(AC+CC)者发生DN的危险较大,OR值为8.569。结论ACE基因/D多态性与2型DM并发DN有关,携带DD基因型和D型等位基因的2型DM患者是DN的易感人群。ATlR基因A1166C多态性虽与我国汉族人2型DM并发DN无关,但AT1R与ACE基因多态存在协同效应,携带AC+CC与DD基因型的个体有更高的患DN风险。     

Relationship between serum IgA/C3 ratio and progression of IgA nephropathy

OBJECTIVE: The serum IgA/C3 ratio might be considered to serve as a diagnostic marker for patients with IgA nephropathy (IgAN), but its value as a marker of the severity of histological lesions or prognosis is unknown. METHODS: We studied the serum IgA/C3 ratio, using standardized reference material, in 86 patients with IgAN and in 32 with non-IgAN. The patients with IgAN were divided according to the severity of histological lesions (mild IgAN, n=29 and severe IgAN, n=57) based on Japanese clinical guidelines. RESULTS: The serum IgA level was significantly higher, while its C3 level was lower in patients with severe IgAN compared to those with non-IgAN. However, these levels were not different between patients with mild IgAN and non-IgAN. In contrast, the serum IgA/C3 ratio obviously differed among the three groups (2.47+/-0.96 vs. 3.63+/-1.44 vs. 4.72+/-1.86; p<0.01, ANOVA). Kaplan-Meier analysis of the patients with IgAN classified according to the mean serum IgA/C3 ratio revealed that the group with high serum IgA/C3 (4.5 and above) had a significantly poorer renal outcome (p<0.05, log-rank test), since the cumulative renal survival rate at 5 years was 84.4% vs. 100%. The ratio (%) of patients with severe IgAN in whom hematuria disappeared, was significantly higher in the low, than in the high serum IgA/C3 group (41.9% vs. 15.4%; p<0.05, t-test). CONCLUSION: The serum IgA/C3 ratio appears to reflect the histological severity of IgAN and could serve as a marker of the progression of IgAN.     

高血压人群中ACE、ADRB1基因多态性与冠状动脉狭窄程度的相关性研究

目的探讨高血压人群中血管紧张素转换酶(ACE)基因多态性及β1肾上腺素能受体(ADRB1)基因多态性与冠状动脉(冠脉)狭窄程度的相关性。方法选取2017年7月至2019年4月于徐州医科大学附属医院心血管内科住院的280例高血压患者的临床资料进行回顾性分析,行冠脉造影或冠脉CT血管造影(CTA)检查判定其是否患有冠心病(CHD),并依据结果判定其冠脉病变支数及给予Gensini评分。根据冠脉检查结果将上述患者分为CHD组(n=145)和对照组(n=135)。所有入选病例均给予了ACE及ADRB1基因多态性检测,并根据结果分为ACE II型纯合子、ID型杂合子、DD型纯合子和ADRB1 GG型纯合子、GC型杂合子、CC型纯合子。结果在研究的高血压人群中,ACE DD基因型携带者在冠脉病变支数中的多支病变组及Gensini得分分组中的重度病变组的占比明显高于ACE II及ACE ID基因型(P<0.05);ADRB1基因多态性在冠脉病变支数分组及Gensini得分分组的对比中无明显相关性(P>0.05);CHD组与对照组一般临床资料对比中显示年龄、高密度脂蛋白胆固醇(HDL-C)和糖尿病与CHD存在相关性,且有统计学意义(P<0.05)。结论ACE基因多态性与高血压人群冠状动脉狭窄程度密切相关,ADRB1基因多态性无明显相关性。     

Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection--association between TGF-beta1 polymorphisms and hepatocellular carcinoma

BACKGROUND/AIMS: In this study, we determined the frequencies of the genotypes associated with the polymorphism of the cytokines genes, and investigated their association with the risk of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) carriers. METHODS: Genetic polymorphism in the cytokines TNF-alpha, IFN-gamma, TGF-beta1, IL-6, and IL-10 were studied in 236 Japanese patients with HBV infection. The genetic polymorphisms of these cytokines were analyzed by polymerase chain reaction-sequence-specific primer (SSP). RESULTS: There was no statistically significant difference in the genetic polymorphisms of TNF-alpha, IFN-gamma, and IL-10 genes between HBV carriers with HCC and those without HCC. However, the TGF-beta1+29 (codon 10) C/C genotype was lower in HBV carriers with HCC than in those without HCC (HCC 14.6% vs non-HCC 31.9%). The association of HCC was significantly lower in HBV carriers with C/C genotype than in those with T/C or T/T genotype in position +29 of the TGF-beta1 gene. CONCLUSIONS: Our findings suggest that the genetic polymorphism in codon 10 of the TGF-beta1 gene may play a role in HCC development in patients with chronic HBV infection.     

血管紧张素系统基因多态性在IgA肾病高血压型和尿检异常型中的分布

目的：根据临床病理表现将IgA肾病（IgAN）分为7种类型。比较高血压型和轻度尿检异常型临床表现及血管紧张素原（AGT）、血管紧张素转化酶（ACE）、血管紧张素Ⅱ受体（AT1R）基因类型分布的差异，及其对IgAN高血压型患者临床表现的影响。方法：PCR法及PCR—RFLP法检测AGT基因M235T多态性、ACE基因I／D多态性、AT1R基因A1166C多态性。回顾性分析IgAN高血压型与轻度尿检异常型患者及IgAN高血压型不同基因型之间临床病理表现的差别。结果：IgAN高血压型患者起病即表现为明显血压升高，肾功能减退，小管功能损害，病理表现出较多球性硬化、间质纤维化等慢性病变，与尿检异常型相比均有统计学意义。在高血压型患者中AGT基因TT、MT、MM基因型分别占65％、28％、7％，T等位基因频率为79％，与尿检异常型相比差异有统计学意义。ACE基因DD型、DI型、Ⅱ型在高血压型患者中分别为15％、54％、31％，与尿检异常型相比差异也有统计学意义，D等位基因频率为42％，显著高于尿检异常型。AT1R基因中，未检测出CC基因型，两组基因型及基因频率相比均无统计学差异。在高血压型患者中，DD基因型及DD＋TT基因型患者起病时血压明显高于其他基因型患者，病理表现亦较重。结论：IgAN高血压型与尿检异常型患者不仅在临床病理表现上有显著不同，在基因背景上也有一定差异，提示IgAN的分型对诊断和治疗均有重要意义。在高血压型患者中，AGTT等位基因及ACED等位基因与血压升高等较重的临床病理表现有密切关联。     

MCP-1 and MIP-1A gene polymorphisms in Japanese patients with sarcoidosis

OBJECTIVES: Monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha exhibit chemotactic activity toward macrophages/monocytes and induce the production of inflammatory cytokines affecting granuloma formation. Recently, a single nucleotide polymorphism (SNP) in the MCP-1 distal regulatory region and a dinucleotide repeat in the MIP-1A gene promoter region were identified. We investigated the relationships between the polymorphisms and susceptibility to sarcoidosis, clinical manifestations, and BALF findings of sarcoidosis. METHODS: The polymorphisms of the MCP-1 and MIP-1A genes in 118 patients with sarcoidosis and 145 healthy control subjects were examined. The MCP-1 polymorphism was genotyped by a PCR-restriction fragment length polymorphism method and the MIP-1A genotype was determined using PCR. RESULTS: No significant difference in the genotype distribution or in the allele frequency between the patients and control subjects was observed. We found no relationship between the polymorphisms and the serum ACE level, organ involvement, roentgenographic stages, or deterioration in chest radiographs during the follow-up. A significant difference in the absolute counts of AMs in BALF of 51 patients among the genotypes of the MCP-1 gene was found (p = 0.048). The AM counts in BALF of the G/A and G/G genotypes were significantly increased compared with that of the A/A genotype (p < 0.05). CONCLUSION: The polymorphisms of the MCP-1 and MIP-1A genes do not play a substantial role in genetic predisposition for sarcoidosis or in clinical manifestations of sarcoidosis in this Japanese population. The MCP-1 SNP might be related to the recruitment of monocytes/macrophages to the alveolar spaces in sarcoidosis.     

Aldose reductase gene polymorphism is associated with progression of diabetic nephropathy in Japanese patients with type 1 diabetes mellitus

Aim: The objective of this study was to investigate cross-sectionally and longitudinally whether polymorphism of the (A-C)n dinucleotide repeat sequence of the aldose reductase ( AR ) gene may modulate risk for diabetic nephropathy or retinopathy in Japanese patients with type 1 diabetes.
Methods: We obtained DNA samples from 101 patients followed up after the onset of type 1 diabetes and analysed a (A-C)n dinucleotide repeat polymorphic marker in the AR gene by polymerase chain reaction (PCR) method.
Results: Ten alleles ranging from Z−10 (128 bp) to Z+8 (146 bp) in repeat number were identified. In cross-sectional studies, the prevalence of the Z+2 allele was higher than that of any other allele in patients with diabetic nephropathy (37.5% of patients in a microalbuminuria group, and 41.7% of those in a macroalbuminuria group including patients with chronic renal failure and maintenance haemodialysis treatment). Prevalence of the Z+2 allele was not increased in patients with diabetic retinopathy. In longitudinal Kaplan–Meier plots, the cumulative incidence of nephropathy was significantly associated with homozygosity for the Z+2 allele (log rank test, p = 0.031); respective prevalence of nephropathy after diabetes durations of 10 and 15 years was 42.9% and 100% in Z+2 homozygotes ( n  = 8), 17.6% and 27.4% in Z+2 heterozygotes ( n  = 44), and 6.1% and 17.4% in patients without the Z+2 allele ( n  = 49). However, occurrence of retinopathy was not influenced by the Z+2 allele (log rank test, p = 0.926).
Conclusions: Homozygosity for the Z+2 allele was associated with accelerated early progression of diabetic nephropathy in Japanese type 1 diabetic patients.     

IgA肾病患者血清低糖基化IgA1水平的变化及其临床意义

目的　探讨IgA肾病患者血清低糖基化IgA1的程度与临床表现、肾脏病理及近期疗效间的关系。方法　用ELISA法对 68例IgA肾病及 2 0例肾病综合征肾小球微小病变 (MCD )患者血清IgA1糖基化程度进行检测 ,并经治疗后随访。 结果　IgA肾病患者蚕豆凝集素与血清IgA1的结合力明显高于对照组 (P <0 .0 2 5 )。IgA肾病患者中 2 0例低糖基化组和 48例正常糖基化组比较 ,前者发病年龄轻、血IgA浓度及肌酐清除率低于后者 (P值均 <0 .0 5 ) ,而病程、尿蛋白排泄量、总胆固醇水平、血压、肾小球病理分级和近期疗效比较差异无显著性 (P值均 >0 .0 5 )。结论　IgA肾病患者血清IgA1呈低糖基化 ,血清低糖基化程度重者发病年龄较轻 ,但肾功能损伤较重 ,血IgA1低糖基化程度不能推测肾脏病理轻重或近期疗效     

Paraoxonase 1 gene polymorphisms concerning non-insulin-dependent diabetes mellitus nephropathy in hemodialysis patients

AimsData on involvement of paraoxonase 1 gene (PON1) in non-insulin-dependent diabetes mellitus (NIDDM) nephropathy are scarce. We investigated PON1 polymorphisms concerning end-stage NIDDM nephropathy and atherosclerotic complications in NIDDM nephropathy patients treated with hemodialysis (HD).MethodsIn NIDDM nephropathy (n = 402) and non-diabetic (n = 998) HD subjects, we obtained PON1 polymorphisms by HRM analysis (rs662) or predesigned TaqMan SNV Genotyping Assay (rs854560, rs705379).ResultsOnly PON1 rs705379 was associated with end-stage NIDDM nephropathy in the recessive (OR 1.451, 95% CI 1.104–1.906, P = 0.009) and additive (OR 1.398, 95%CI 1.009–1.936, P = 0.046) inheritance modes. NIDDM nephropathy patients bearing the rs854560 T allele were at higher risk for ischemic cerebral stroke (OR 2.087, 95%CI 1.145–3.801, P = 0.016). In non-diabetic patients but not NIDDM nephropathy subjects, atherogenic dyslipidemia corresponded with PON1 rs662 A allele and PON1 rs854560 TT homozygosity.ConclusionsIn HD patients, NIDDM nephropathy correlates with the TT genotype of PON1 rs705379. The rs854560 T allele indicates a higher risk for atherosclerotic diseases in NIDDM nephropathy subjects. The T alleles of both PON1 SNVs are known as low expression variants downregulated serum PON1 activity. An increase of diminished PON1 activity may be a target in the prevention of NIDDM nephropathy and NIDDM atherosclerotic complications.     

Increased frequency of the heterozygous switch region of IgA2 in Japanese patients with IgA nephropathy.

The relation between IgA hyperproduction and restriction fragment length polymorphism (RFLP) of the immunoglobulin heavy chain switch (S) region was examined in Japanese patients with IgA nephropathy (IgAN) using Southern blot hybridization. Polymorphism in the S regions of IgM, IgA1 and IgA2 (SA2) was detected. A significant increase in the frequency of heterozygous phenotype of SA2 was shown in the patients. These patients showed a significant increase in the amount of serum IgA, IgA bearing cells and levels of proteinuria. Although two reports on RFLP of the S region have been published in Europe, the results differed. A comparison of the three reports showed different frequencies in the phenotype of the S region between Caucasian and Japanese patients. These results suggested that there is heterogeneity at the S region in IgAN patients in various countries and that this polymorphism might be associated with IgA hyperproduction and the development of proteinuria in Japanese patients.     

广西巴马长寿人群ACE基因多态性与环境因素的交互作用

目的 探讨血管紧张素转换酶(ACE)基因I/D多态性与环境因素在巴马地区长寿现象发生中的交互作用.方法 采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术对广西巴马地区200例长寿老人(年龄90～110岁,长寿组)以及288例健康成年人(年龄48～89岁,对照组)的ACE基因进行基因分型.应用条件Logistic回归模型分析巴马长寿发生的环境及遗传因素,根据交互作用指标判断基因与环境的交互作用.结果 长寿区的环境因素及ACE基因的ID+DD基因型是巴马人长寿的促进因素,两者存在交互作用(OR=11.063,r=1.378).结论 ACE基因I/D多态性与环境因素在巴马地区长寿现象发生中存在一定的交互作用,其长寿现象的发生是遗传及环境因素共同作用的结果.     

Glomerular tip adhesions predict the progression of IgA nephropathy

Background

Focal segmental glomerulosclerosis-like lesions have been proposed to be predictive factors for IgA nephropathy. This single center, retrospective cohort study was designed to clarify which clinical and pathological factors are predictive of decreased estimated glomerular filtration rate (eGFR) at 5 and 10 years in IgA nephropathy patients.

Methods

Of the 229 patients with IgA nephropathy who were admitted to Aichi Medical University Hospital between 1986 and 2010, 57 were included in this study during the 5 to 10 years after renal biopsy. Clinical, laboratory, and pathological parameters were analyzed by multiple linear regression analysis with backward elimination to determine independent risk factors. After identifying such factors, we compared patients with and without each factor using the Student’s t test, Wilcoxon test, or Mann–Whitney U test.

Results

Four variables were identified as predictive factors for progression of IgA nephropathy: initial eGFR (p?=?0.0002), glomerular tip adhesion (p?=?0.004), global sclerosis (p?=?0.019), and diastolic blood pressure (p?=?0.024). The annual decrease in eGFR of patients with (n?=?9) or without glomerular tip adhesions (n?=?48) was 4.13?±?3.58 and 1.49?±?2.89 ml/min/1.73 m2, respectively (p?=?0.015). Serum total cholesterol levels were 231?±?45 mg/dl and 196?±?42 mg/dl, respectively (two-sided p?=?0.064; one-sided p?=?0.032).

Conclusions

The presence of glomerular tip adhesions predicts the progression of IgA nephropathy. High levels of serum total cholesterol may affect glomerular tip adhesions.

     

Differential effects of RAS inhibitors associated with ACE gene polymorphisms in type 2 diabetic nephropathy

Blood pressure and genetic factors are important factors for diabetic nephropathy. We investigated the relationship between the efficacy of renin angiotensin system (RAS) inhibitors and angiotensin-converting enzyme (ACE) genotypes. Patients with type 2 diabetes without proteinuria, were treated with RAS inhibitors, the first being an ACE inhibitor (ACEI) and the second, an angiotensin II (ATII) receptor blocker (ARB) for 8 weeks each. There was no significant difference (except serum ACE activity) between the two treatments. However, by analysis segregated with ACE gene polymorphism, ARB significantly decreased transforming growth factor-beta1 (TGF-beta) compared to ACEI in patients with the I/I genotype but not in patients with the D/I+D/D genotype. DeltaATII and DeltaTGF-beta have a negative correlation with the I/I genotype and a positive correlation with the D/I+D/D genotypes. These correlation coefficients are significantly different. We suggest that in I/I patients, TGF-beta was reduced by ARB via effects on (ATII) type 2 receptors (AT2). In our experiments, the effect of ARB on TGF-beta reduction was only detected by segregation of ACE genotypes. This indicates that the selection of medicine in light of a patient's genotype is important in treating diabetic nephropathy.     

脑出血患者载脂蛋白E和血管紧张素转换酶的基因多态性分析

目的探讨载脂蛋白E（apoliportein E,ApoE）和血管紧张素转换酶（angiotensin converting enzyme,ACE）基因多态性与脑出血的关系。方法应用聚合酶链反应-限制性片断长度多态性技术检测80例脑出血患者和90名健康对照者的ApoE和ACE基因型和等位基因。并运用Logis-tic回归分析ApoE和ACE基因多态性与脑出血的相关性。结果脑出血组ApoE的基因型频率和等位基因频率与正常对照组比较,差异均无统计学意义,P〉0.05;ACE的DD基因型频率为35.0%,D等位基因频率为51.9%,明显高于正常对照组的15.6%、38.9%,均P〈0.05;Logistic回归分析显示,ACE的DD基因型的患者患脑出血的OR值为2.923（95%CI：1.406-6.079）;同时携带ACE基因DD型和ApoE E3/4基因型的患者患脑出血的OR值为3.428（95%CI：1.045-11.237）。结论ACE基因插入/缺失多态性可能是脑出血发病的独立遗传因素;与ApoE基因多态性间具有协同致脑出血的作用。     

进展型(重症)IgA肾病12例临床与病理分析

目的通过对12例进展型(重症)IgA肾病患者临床和病理资料的分析,试图发现IgA肾病进展的危险因素。方法选取我院近年来行肾穿刺活检时即出现肾功能减退和(或)随访过程中肾功能进行性减退的IgA肾病患者12例进行分析。结果12例患者中就诊原因分别为眼睑、下肢水肿,尿中泡沫增多或反复发作无痛性肉眼血尿或体检发现蛋白尿和(或)高血压及肾功能减退。病程20天~9年,平均病程3年。所有患者均有蛋白尿、其中肾病综合征5例;病程中反复发作肉眼血尿5例,其中伴肾病综合征和大量蛋白尿3例;蛋白尿 镜下血尿6例。肾功能损害轻度~重度,CKD(慢性肾脏疾病)1~4级;Ccr94ml/min~25.9ml/min;病理所见均为IgANⅣ级,以增生、硬化及新月体为主。完全缓解1例,进展为终末期肾衰竭2例,部分缓解3例,1例5年前肾活检时肾功能基本正常,病理改变较轻,失访5年后再次就诊时肾功能已减退,其余病例正在治疗随访中。结论部分IgA肾病患者病情进展迅速,尤其是反复发作肉眼血尿伴大量蛋白尿和(或)肾病综合征(NS)及免疫复合物在血管襻沉积者,可能是IgA肾病进展的危险因素。一旦确诊,应根据病理所见进行相应的免疫抑制治疗。积极治疗可以有效的控制IgA肾病的进展。