68例维吾尔族IgA肾病患者MBL基因多态性与临床病理相关性分析

目的 探讨甘露糖结合凝集素(mannose-binding lectin,MBL)基因第54位密码子多态性与维吾尔族IgA肾病患者临床和病理的关系.方法 应用PCR-RFLP方法对68例维吾尔族IgAN患者进行MBL多态性检测,并与患者临床和病理特点进行相关性分析.结果 ①维吾尔族IgAN中表现为蛋白尿的患者突变型等位基因GAC的发生频率显著高于表现为单纯血尿的患者(P＜0.05);②维吾尔族IgAN中表现为复合性免疫沉积的患者等位基因GAC的发生频率显著高于表现为单纯免疫沉积的患者(P＜0.05).结论 MBL突变型等位基因GAC与维吾尔族IgAN 蛋白尿发生和免疫复合沉积相关.     

用PCR-SSO检测IgA肾炎HLA-DRB1、DQA1、DQB1等位基因及其临床意义

利用聚合酶链区应（PCR）和序列特异性寡核苷酸（SSO）探针技术对47例经临床及免疫荧光证实的IgA肾病（IgAN）患者HLA-DRB1、DQA1、DQB1等位基因频率进行了检测。结果显示IgAN患者组DR4基因频率明显高于正常人组,相反DQB1*0602基因频率与对照组相比呈显著下降。IgAN患者中蛋白尿组DR4基因频率显著高于对照组,而肉眼血尿组与对照组无显著差异。约 1/4 DR4基因阳性的IgAN病理表现为局灶节段硬化性肾小球肾炎。 IgAN肾衰组DR4阳性的发生率显著高于非肾衰组。由此可见,IgAN中HLA-DR4基因频率而著增高, DR4阳性IgAN临床多表现蛋白尿,易发生肾衰,病理多呈局灶节段硬化型;DQB1*0602等位基因对IgAN可能有一定抵抗性。这些研究结果提示IgAN有免疫遗传的背景。     

Transforming growth factor-beta1 gene polymorphism modifies the histological and clinical manifestations in Japanese patients with IgA nephropathy

Transforming growth factor (TGF)-beta1, a multifunctional cytokine, which regulates proliferation and differentiation of a variety of cell types, has the central role in the development and progression of renal injury in both animal models and human. Although it has been suggested that genetic variations in the TGF-beta1 gene are associated with the activity of the gene product, their clinical significance in glomerular disease is unknown. We investigated whether the polymorphisms of C-509T and T869C in TGF-beta1 account for interindividual variation in manifestations of IgA nephropathy (IgAN) using 626 Japanese subjects including 329 patients with histologically proven IgAN and 297 healthy controls with normal urinalysis. The frequencies of genotypes, alleles, and major haplotypes were similar between the patients and controls. The C-509T and T869C polymorphisms were in tight linkage disequilibrium, and the major haplotypes were C-C and T-T, which accounted for more than 95% of the total. In patients with -509CC and in those with the 869CC, urinary protein excretion was higher than in those with other genotypes, whereas no difference in other clinical manifestations was noted. Moreover, patients with -509CC and those with 869CC genotypes presented with a significant higher score of mesangial cell proliferation than in those with other genotypes. These results suggest that TGF-beta1 gene polymorphisms are specifically associated with heavy proteinuria and mesangial cell proliferation in Japanese patients with IgAN, although they do not confer susceptibility to this disease.     

Disease progression, response to ACEI/ATRA therapy and influence of ACE gene in IgA nephritis

Various studies have shown that angiotensin-converting enzyme （ACE） gene insertion/deletion （ID） polymorphism may play a role in the progression to end stage renal failure （ESRF） in patients with IgA nephritis （IgAN）. In this randomized controlled trial, patients were followed up for 5 years to determine their long-term renal outcome to ACEI/ATRA therapy and to ascertain if their ACE gene profile could play a role in determining their response to therapy. Seventy-five patients with IgAN were enlisted. Thirty-seven were on ACEI/ATRA therapy for 62 ± 5 months and thirty-eight were untreated and served as controls. All patients had their ACE gene ID polymorphism genotyped. Compared to controls, treated patients had lower serum creatinine （p 〈 0.001）, lower proteinuria （p 〈 0.002） and fewer numbers progressing to ESRF （p 〈 0.002）. Among patients with genotype II, there were less ESRF in the treatment group when compared to the untreated control group （p 〈 0.02）. The advantage of therapy was not seen in patients with ID or DD genotypes. ACEI/ATRA therapy was found to be effective in retarding disease progression in IgAN with years to ESRF significantly extended in patients at all levels of renal function, including patients whose outcome were ESRF. Genotyping showed better response to therapy only for those with genotype Ⅱ. The common mechanism is probably through lower levels of ACE, glomerular pressure and proteinuria resulting in reduced renal damage and retardation of progression to ESRF. Cellular ＆ Molecular Immunology.     

内蒙古汉族IgA-N患者TNF-α基因多态性与临床特征、病理类型及预后关系的研究

目的:在内蒙古开展汉族IgA肾病(IgA-N)患者TNF-α基因多态性与临床特征、病理类型及预后关系的研究。方法:选100例内蒙古汉族IgA-N患者(对其中33例患者进行1月～60月的随访)及105例正常对照组,采用聚合酶链式反应-限制性片段长度多态性分析(PCR-RFLP)技术检测TNF-α基因多态性和等位基因频率,分析不同基因型与IgA-N临床特征、病理类型及预后的关系。结果:①IgA-N患者TNF-α的三种基因型与健康对照组间差异无显著性(P>0.05)。②TNF-α的三种基因型与IgA-N患者的年龄、血压、血尿、尿蛋白、白蛋白、肾功能及病理间无显著关系。③多因素logistic回归分析表明,高血压病史、蛋白尿是除TNF-α基因型、Haas分级及发病时年龄外引起肾脏损害加重的独立危险因素。④采用Cox比例风险模型将多因素对预后的影响进行分析,结果显示,TNF-α不同基因型、发病时CCr水平是除蛋白尿、Haas分级、高血压病史和肉眼血尿以外影响IgA-N患者预后的独立危险因素。⑤TNF-α的Kaplan-Meier生存曲线显示,以肾穿为零点,各种TNF-α基因型的患者在肾穿后肾功能的下降倾向于TNF-α1/2基因型最快,TNF-α1/1基因型次之,TNF-α2/2最慢。结论:①高血压病史、蛋白尿是除TNF-α基因型、Haas分级及发病时年龄外引起肾脏损害加重的独立危险因素;②TNF-α不同基因型、发病时CCr水平是除蛋白尿、Haas分级、高血压病史和肉眼血尿以外影响肾病患者预后的独立危险因素;③TNF-α1/2基因型可能是IgA-N慢性化进展的危险因子之一。     

中国甘肃汉/ 回族人群C1GALT1、DEFA 基因多态性与IgA 肾病易感性的关系

目的:探讨β-1,3鄄半乳糖基转移酶(C1GALT1)基因rs1008898 位点及琢防御素(α-defensin,DEFA) 基因rs2738081 位点多态性与中国甘肃省汉族人群和回族人群IgA 肾病易感性的关系,筛查预测IgA 肾病的分子标记。方法:本研究选取甘肃地区患IgA 肾病的汉族个体146 例、回族个体83 例作为实验组,另选取健康汉族个体180 例、健康回族个体100例作为对照组。采用聚合酶链反应鄄限制性片段长度多态性(Polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP) 方法以及PCR 产物基因测序法对单核苷酸多态性基因位点进行基因分型,采用卡方检验比较各基因型、等位基因在病例组和对照组中的分布差异,评价各基因型、等位基因与IgA 肾病发病风险的关系。结果: 汉族IgA 肾病患者rs1008898 位点的GG 基因型频率与健康对照组之间有统计学差异(OR=2.489,95CI:1.259 ~4.922,字2 =7.037,P =0.008),且G 等位基因可能增加患IgA 肾病的风险(OR = 1.268,95% CI:1.056 ~ 1.523,字2 = 6.709,P = 0.01)。回族IgA 肾病患者rs1008898 位点的多态性与健康对照组之间差异无统计学意义(P>0.05)。(3)rs2738081 位点多态性在汉族、回族IgA 肾病患者及其健康对照组之间的分布差异无统计学意义(P>0.05)。结论:rs1008898 位点G 等位基因可能增加甘肃地区汉族人群患IgA 肾病的风险。     

DRD1基因4个多态性位点与注意缺陷多动障碍的关联分析

目的:探讨ADHD与DRD1基因4个多态性(G-48A,G-1251C,T-800C和T1403C)单个位点的关系.方法:对138名ADHD患者和119名正常对照进行以下遗传学分析:应用PCR-限制性内切酶分析技术分析4个SNP位点,检测各位点基因型和等位基因频率,经χ~2检验比较两组间各位点基因型及等位基因频率的差异.结果:①ADHD组中DRD1基因G-48A多态性-48C/-48G基因型频率明显低于对照组,差异有统计学意义(χ~2=4.318,P=0.045).②ADHD组和对照组在DRD1基因的其他3个多态性位点(G-1251C、T-800C和T1403C)等位基因和基因型频率分布均无统计学差异(P>0.05)).结论:①DRD1基因G-48A多态性与ADHD可能存在关联.-48G/-48G基因型可能是ADHD的保护因素.②DRD1基因的其他三个SNP(G-1251C,T800C和T1403C)与ADHD可能均无关联.     

Is tumor necrosis factor genotype (TNFA2/TNFA2)a genetic prognostic factor of an unfavorable outcome in IgA nephropathy?

The purpose of this study was to examine whether there are the associations between TNF alpha and TNF beta gene polymorphisms and the development and progression of Ig A nephropathy (IgAN). A cross-sectional study on TNF alpha and TNF betagene polymorphisms by polymerase chain reaction with restriction fragment length poly-morphisms was performed on 76 patients with primary IgAN confirmed by renal biopsy and 100 healthy controls. The allele with G-->A substitution was designated as TNFA2 for the TNF alpha gene and TNFB2 for the TNF betagene. A patient in whom dialysis treatment was started or whose serum creatinine became double or over during the follow-up duration was designated as a "progressor". The TNFA2/ TNFA2 genotype was more prevalent in the progressor than in the non-pregressor group (20.0 vs 3.3%, p<0.05). Clinical factors such as serum creatinine, systolic and diastolic blood pressure (p<0.001, respectively) were higher and pathologic factor such as Grade IV or V renal lesions was more prevalent (p<0.01) in the progressor than in the non-progressor group. Therefore, TNFA2/TNFA2 genotype may be a risk factor for the progression of IgAN.     

Association of the brain-derived neurotrophic factor gene G196A rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia

This study aimed to explore the association between BDNF G196A gene rs6265 polymorphisms and the cognitive function and clinical symptoms of schizophrenia. Methods: BDNF G196A rs6265 genotype and allele frequency were measured using Polymerase Chain Reaction (PCR) methods in 224 drug-free patients with schizophrenia and 220 controls. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), and cognitive functioning was assessed using the Wisconsin Card Sorting Test (WCST) and the Trail Making Test (TMT). In the patient group, differences in severity of symptoms across the three genotypes (i.e., G/G, G/A and A/A) of G196A were assessed using one-way analysis of variance. Results G/A genotype had higher frequencies than GG or AA genotype in both patients and controls. There was no significant difference in G/G, G/A, A/A genotype frequency between patients and controls (P > 0.05). The allele G had higher frequencies than allele A in both patients and controls. There was no significant difference in G or A allele frequency between patients and controls (P > 0.05). There was significant difference in A/A genotype frequency between positive group patients and negative group patients. There was no significant difference in cognitive performance between patients with G/G, G/A and A/A genotype (all P > 0.05). Conclusion BDNF G196A gene rs6265 polymorphism is not associated with the cognitive function but with the clinical symptoms of schizophrenia.     

Aberrant sialylation of serum IgA1 was associated with prognosis of patients with IgA nephropathy

Aberrant glycosylation of serum IgA1 was considered as an initial event and involvement in the pathogenesis of IgAN. We previously demonstrated that aberrant glycosylation of serum IgA1 was associated with pathologic phenotype of IgAN. The present study is to investigate if abnormal sialylation of IgA1 affects renal survival of IgAN. 127 patients with biopsy-proven IgAN were enrolled and followed up to 8 years. Seventy-nine healthy and 75 patients with non-IgAN renal diseases were selected as controls. Alpha 2, 6 sialic acid (SA) of serum IgA1 was measured by sandwich-ELISA. Renal survival rate was estimated by Kaplan-Meier method. Alpha 2, 6 SA level in patients with IgAN was lower than that in healthy controls (0.92+/-0.14 vs. 0.98+/-0.12, P=0.001) and non-IgAN glomerulonephritis (0.92+/-0.14 vs. 1.00+/-0.18, n=53, P=0.001). Patients with IgAN in Low SA Group were no significant differences compared with patients in Normal SA Group in age, gender, hypertension, serum creatinine, and excretion of proteinuria. Renal cumulative survival rate was 53.3% in patients in Low SA Group and 83.5% in Normal SA Group (P=0.0008). The lower the alpha 2, 6 SA level of serum IgA1 in patients with IgAN was, the worse their renal survival rate was. Although patients in Low SA Group had worse renal function evaluated by eGFR, there was no significant difference in various CKD stages in non-IgAN renal function controls (n=42, P=0.352). Alpha 2, 6 SA level of serum IgA1 was associated with the prognosis of patients with IgAN and could serve as a predictor of poor prognosis in IgAN.     

PAI-1基因4G4G基因型与IgA肾病易感性及临床表现的关系

目的探讨PAI-1基因启动子区4G／5G多态性与IgA肾病的发生、进展和临床表现的关系。方法收集IgA肾病患者的临床资料；应用PCR-限制性片段长度多态技术分析296例IgA肾病患者和310名健康人的PAI-1基因4G／5G多态性；分析PAI-1基因4G／5G多态性与IgA肾病的发生与临床表现及病理改变的关系。结果（1）PAI-1基因4G4G，4G5G，5G5G基因型频率在IgA肾病组和正常对照组分别为0．33、0．19、0．48和0．3、0．23、0．47，两组之间差异无统计学意义（X^2=1．63，P〉0．05）；（2）4G4G纯合子基因型频率在病理Lee氏分级Ⅲ级以下组（A组）和Ⅳ～Ⅴ级组（B组）分别为0．39和0．28，（X^20=7．86，P〈0．05）。（3）按基因型分组，4G4G组IgA肾病患者的肌酐清除率明显低于非4G4G组；4G4G组患者的血清甘油三酯水平明显高于5G5G组；4G4G组患者高甘油三酯血症发生率明显高于4G5G组（P〈0．05）。结论PAI-1基因启动子区4G／5G多态性不是IgA肾病发生的易感因素，但可能是IgA肾病病情加重的危险因子。     

Polymorphisms of the <Emphasis Type="Italic">IL23R</Emphasis> Gene Are Associated with Psoriasis but not with Immunoglobulin A Nephropathy in a Hungarian Population

Recently, associations were found between autoimmune diseases and variants of interleukin-23 receptor (IL23R) gene; here, we analyzed the association of nine IL23R polymorphisms with psoriasis and with immunoglobulin A nephropathy (IgAN). Groups of patients with psoriasis, IgAN, and controls were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) methods. We observed a significant increase in the carriage of the minor allele of rs11805303 in psoriasis patients compared to controls. Similarly, for rs2201841 prevalence of the CC genotype and for rs10889677, the AA genotype showed a more than two- and threefold increase, respectively in patients compared to controls. There was no difference in the distribution of IL23R variants between controls and IgAN patients. We confirmed the association of IL23R with psoriasis in a Hungarian population and demonstrated the effect of the rs11805303 SNP, which was tested so far only for other autoimmune diseases. We could not detect any association between the IL23R variants and IgAN.     

Association between lymphotoxin beta receptor gene polymorphisms and IgA nephropathy in Korean children

Lymphotoxin beta receptor (LTBR) is essential for development and organization of the secondary lymphoid tissues. To investigate whether LTBR polymorphisms are associated with IgA nephropathy (IgAN) in Korean children, One hundred ninety nine patients with IgAN and 289 controls were recruited. Two promoter single nucleotide polymorphisms (SNPs) (rs3759333, -1387C/T and rs3759334, -1326A/G) and one coding SNP (rs2364480, Ala172Ala) in LTBR gene were selected and genotyped by direct sequencing. For analysis of data, SNPStats, SPSS 18.0, and Haploview version 4.2 were used. Multiple logistic regression models (codominant 1, codominant 2, dominant, and recessive models) were performed for odds ratio (OR), 95% confidence interval (CI), and p value. The rs3759334 was significantly associated with IgAN in codominant 1 (G/G vs. A/G, p = 0.025) and dominant (p = 0.017) models. The A alleles of rs3759334 and rs2364480 were related to risk of developing IgAN, respectively (rs3759334, p = 0.015; rs2364480, p = 0.041). Haplotypes CGC and TAA in LTBR gene were also associated with IgAN, respectively (CGC, p = 0.032 in codominant; TAA, p = 0.008 in codominant, p = 0.009 in dominant models). In conclusion, results suggest that LTBR gene polymorphisms may be associated with risk of IgAN in Korean children.     

Urinary mannose-binding lectin is a biomarker for predicting the progression of immunoglobulin (Ig)A nephropathy

Complement system activation is associated with immunoglobulin A nephropathy (IgAN) activity and progression. The aim of the present study was to investigate the importance of urinary mannose-binding lectin (MBL), at the time of renal biopsy, for evaluating disease severity and predicting the progression of IgAN. A total of 162 patients with biopsy-proven IgAN were enrolled and 50 healthy individuals were selected as normal controls. Urinary MBL was measured by sandwich enzyme-linked immunosorbent assay (ELISA) and normalized for urinary creatinine concentration. Urinary MBL was significantly higher in IgAN patients than that in normal controls, and elevated as histopathological phenotypes upgraded. Urinary MBL was correlated significantly with the well-known clinical predictors for the prognosis of IgAN; that is, renal function (represented by serum creatinine and estimated glomerular filtration rate), proteinuria and arterial hypertension. Urinary MBL was demonstrated to be correlated with the histopathological parameters which have independent value in predicting renal outcome of IgAN according to the Oxford classification; that is, mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity and tubular atrophy/interstitial fibrosis. More importantly, non-remission patients at the end of follow-up had significantly higher levels of urinary MBL compared with patients in remission. In conclusion, urinary MBL can be a reliable non-invasive biomarker for evaluating disease severity and predicting the prognosis of IgAN. This is the first report on this issue. However, our conclusions should be verified further in large-scale studies with long-term follow-up.     

4G/5G plasminogen activator inhibitor-1 and −308 A/G tumor necrosis factor-α promoter gene polymorphisms in Argentinean lupus patients: focus on lupus nephritis

We investigated the relationship between the 4G/5G plasminogen activator inhibitor (PAI-1) and ?308 A/G tumor necrosis factor-α (TNF-α) polymorphisms and the clinical and biochemical features of systemic lupus erythematosus (SLE) in an Argentinean patient cohort. A total of 402 patients were studied, including 179 SLE patients and 223 healthy individuals. PCR-RLFP was used to determine the genotypes of the 4G/5G PAI-1 and ?308 A/G TNF-α polymorphisms. SLE patients with lupus nephritis (LN) (n = 86) were compared with patients without LN (n = 93). Additionally, LN patients were divided into proliferative LN and non-proliferative LN groups according to the results of the renal biopsies. No significant differences were noted in the genotype distributions or allele frequencies of these TNF-α and PAI-1 polymorphisms between SLE patients and controls. There were higher numbers of criteria for SLE, more lupus flares and higher damage scores in LN patients, but there were similar frequencies of anti-phospholipid antibody (APA) positivity and anti-phospholipid syndrome. No significant difference was noted for any studied variable between the proliferative LN and non-proliferative LN groups except for the presence of APA. We found no significant differences in the TNF-α and PAI-1 genotype distributions or allele frequencies between groups. We found that the ?308 A/G TNF-α and 4G/5G PAI-1 polymorphisms are not associated with susceptibility to SLE in an Argentinean population. We also did not find any association between the presence of any specific allele or genotype and the development of LN in SLE patients. Finally, no association was noted between either of the two polymorphisms and the severity of renal disease.     

Polymorphisms of insulin-like growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) contribute to pathologic progression in childhood IgA nephropathy

Previous studies have suggested that insulin-like growth factor-1 (IGF-1) signaling might play an important role in renal fibrosis and regulation of the proliferation of mesangial cells and podocytes. We conducted the present study to investigate association between single nucleotide polymorphisms (SNPs) of IGF-1 (IGF-1) and IGF-1 receptor (IGF-1R) genes and childhood immunoglobulin (Ig) A nephropathy (IgAN). We analyzed five SNPs of IGF-1 and IGF-1R in 188 pediatric IgAN patients and in 263 healthy controls. We compared variations in SNPs in several sets of IgAN subgroups that were designated based on the presence of nephrotic range proteinuria (>40 mg/m2 per h), podocyte foot process effacement, and pathological progression. Genotyping of IgAN patients and controls revealed differences in IGF-1R rs2229765. Moreover, the rs2195239, rs978458, and rs1520220 SNPs of IGF-1 showed significant association with pathological progression. Thus, in the present study, we observed associations between the IGF-1/1R pathway, susceptibility to IgAN, and the pathologic progression of IgAN.