Association of angiotensinogen gene M235T polymorphism with the risk of IgA nephropathy: a meta-analysis

The association between angiotensinogen (AGT) M235T gene polymorphism and IgA nephropathy (IgAN) risk remains elusive. Our aim was to evaluate the association between AGT M235T gene polymorphism and IgAN susceptibility by performing a meta-analysis. Eligible studies were searched according to predefined criteria using electronic databases. Eight studies were identified for the analysis of the association between AGT M235T gene polymorphism and IgAN risk. M allele/MM genotype were not associated with IgAN risk in overall populations, Caucasians and Asians (overall populations: p?=?0.448 and 0.861, Caucasians: p?=?0.618 and 0.886, Asians: p?=?0.566 and 0.652). TT/MT genotype were not associated with IgAN risk in overall populations, Caucasians and Asians (overall populations: p?=?0.703 and 0.454, Caucasians: p?=?0.975 and 0.946, Asians: p?=?0.697 and 0.353). No evidence of publication bias was observed. In conclusion, AGT M235T gene polymorphism may not be correlated with IgAN susceptibility in overall populations, Caucasians and Asians. However, more studies should be performed in the future.     

Methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and diabetic nephropathy susceptibility in patients with type 2 diabetes mellitus

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is a crucial enzyme that regulates nucleotide synthesis and DNA methylation. The MTHFR C677T gene polymorphism (rs1801133), a C?→?T transition at nucleotide 677 in exon 4, is a common gene variant of MTHFR and has been implicated in diabetic nephropathy, albeit with inconsistent results. Here, we performed a meta-analysis to assess the common effect size of this polymorphism on DN susceptibility. Case–control studies on the association of the MTHFR C677T gene polymorphism with DN risk were retrieved from databases up to August 1, 2013, and eligible studies were recruited into the meta-analysis and further analyzed. Of 132 studies, 33 were identified as suitable for this analysis. The results showed that T allele and TT genotype were distinctly associated with DN susceptibility in the overall population and Asians, and might be a risk factor in Caucasians and Africans (T allele: Overall population: p?<?0.00001, Asians: p?=?0.0002, Caucasians: p?=?0.02, Africans: p?<?0.00001; TT genotype: Overall population: p?<?0.00001, Asians: p?=?0.0003, Caucasians: p?=?0.008, Africans: p?=?0.0003). Furthermore, the analysis suggested that the CC genotype might play a protective role against DN onset in patients with type 2 diabetes for the overall population, Asians, Caucasian and Africans. However, due to the limited sample size in the African population, these results should be interpreted with care. In conclusion, the MTHFR C677T T allele or TT genotype might be a significant genetic molecular marker to determine the risk of DN in patients with type 2 diabetes and help to develop suitable disease prevention and management strategies.     

Association of AGT M235T gene polymorphism with HSP/HSPN risk

Abstract

To evaluate the association between angiotensinogen (AGT) gene polymorphism and the risk of Henoch–Schönlein purpura (HSP)/Henoch–Schönlein purpura nephritis (HSPN) we searched the eligible studies through Pub Med, Embase, Cochrane, and China National Knowledge Infrastructure (CNKI) databases according to predefined criteria. A random-effects model was used to calculate the combined odds ratios (ORs) and its corresponding 95% confidence interval (CI). Five studies were recruited for the analysis of the association between AGT M235T gene polymorphism and HSP/HSPN risk. M allele was associated with lower risk of HSP in adult (p?=?0.050), TT genotype was associated with the susceptibility to HSP in adult (p?=?0.039). AGT M235T gene polymorphism was not associated with HSP risk in children. No marked association was observed between AGT M235T gene polymorphism and HSPN risk. No evidence of publication bias was observed. In conclusion, M allele might be a protective factor against the HSP risk in adult, TT genotype might be a risk factor for the susceptibility to HSP in adult. However, further larger studies should be performed in the future.     

Monocyte chemoattractant protein-1 -2518G/A gene polymorphism and the risk of nephropathy in type 2 diabetes mellitus among Asians: a meta-analysis

The association between monocyte chemoattractant protein-1 (MCP-1) -2518G/A gene polymorphism and the risk of nephropathy in type 2 diabetes mellitus (T2DM) remains controversial. A meta-analysis was conducted to assess the association of MCP-1 -2518G/A gene polymorphism with the risk of nephropathy in T2DM. Eight studies were included in our meta-analysis by searching electronic databases according to predefined criteria. No significant association between G allele, GG genotype, or AA genotype and the onset of nephropathy in T2DM was observed among Asians. GA genotype was significantly associated with nephropathy risk in T2DM among Asians (p?=?0.024). MCP-1 -2518G/A gene polymorphism was not associated with nephropathy risk in T2DM among Chinese, Koreans, and Turks. For Indians, G allele and AA genotype were not associated with nephropathy risk in T2DM, GG genotype was associated with a lower risk of nephropathy in T2DM (p?=?0.017), GA genotype was associated with the susceptibility of nephropathy in T2DM (p?=?0.029). In conclusions, GA genotype might be a risk factor for the onset of nephropathy in T2DM among Asians, particularly Indians; GG genotype seems to be a protective factor against the susceptibility of nephropathy in T2DM among Indians.     

Megsin 2093T-2180C haplotype at the 3' untranslated region is associated with poor renal survival in Korean IgA nephropathy patients

AIMS: Megsin is a mesangial cell-predominant gene which belongs to the serpin superfamily. The expression of megsin was upregulated and coincided with mesangial proliferation and extracellular matrix expansion in IgA nephropathy (IgAN). In the present study, we evaluated the influence of the C2093T and C2180T polymorphism within the 3' untranslated region (3'UTR) of megsin gene and its haplotypes on the development and progression of Korean IgAN patients. METHODS: Korean IgAN patients (n = 260) with a minimal follow-up of 4 years were recruited. Healthy subjects with normal renal function, normal urinalysis and normotension (n = 315) were included as controls. The polymorphisms were determined by the 5' nuclease allelic discrimination assay, and the haplotypes were constructed using the Phase program. RESULTS: The C2093T and C2180T genotype and allele frequencies were not different significantly between IgAN patients and controls. In C2093T polymorphism, patients with CC genotype showed a better renal survival than those with CT or TT genotypes by Kaplan-Meier analysis (p = 0.027). The megsin C2093T polymorphism remained an independent risk factor for progression (Cox regression model, HR for TT genotype: 3.52, 95% CI 1.69 - 7.34; HR for CT genotype: 2.15, 95% CI 1.30 - 3.57). In C2180T polymorphism, patients with TT genotype showed a better outcome than those with CC or CT genotypes (p = 0.025). The C2180T polymorphism was also an independent risk factor for progression (HR for CC genotype: 4.05, 95% CI 1.93 - 8.51; HR for CT genotype: 2.35, 95% CI 1.40 - 3.94). The two alleles showed linkage disequilibrium in phased haplotype. The patients with 2093T-2180C haplotype showed a poor renal survival compared to those with 2093C-2180T haplotype (p = 0.028). The haplotype remained an independent risk factor for progression (HR for 2093T-2180C haplotype: 2.01, 95% CI 1.44 - 2.81). CONCLUSIONS: Our results suggest that the 2093T-2180C haplotype at the 3'UTR of megsin gene is associated with rapid disease progression in Korean IgAN patients. This is the reverse of the results from the Chinese IgAN patients. Further studies are strongly needed to elucidate the reasons of disparity.     

Association of the methylenetetrahydrofolate reductase gene C677T polymorphism with the risk of male infertility: a meta-analysis

Several molecular epidemiological studies have been conducted to examine the association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and male infertility susceptibility, but the results remain inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. In this meta-analysis, a total of 26 case–control studies including 5659 infertility cases and 5528 controls were selected to evaluate the possible association. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were used to assess the strength of association of C677T polymorphism with male infertility in the additive model, dominant model, recessive model and allele-frequency genetic model. In the overall analysis, the frequency of the 677T allele was significantly associated with male infertility susceptibility (OR?=?2.32, 95%CI?=?2.04–2.65 for TT vs. CC genotype; OR?=?1.09, 95%CI?=?1.00–1.19 for CT vs. CC genotype; OR?=?1.19, 95%CI?=?1.10–1.29 for CT/TT vs. CC genotype; OR?=?1.54, 95%CI?=?1.36–1.74 for TT vs. CC/TT genotype; OR?=?1.22, 95%CI?=?1.15–1.30 for T vs. C allele). A subgroup analysis of the subjects showed that significantly strong association between MTHFR C677T polymorphism and male infertility was present only in Asians, but not in Caucasians. Additionally, MTHFR C677T was associated with a significant increase in the risk of azoospermia in all genetic models. Meanwhile, no significantly increased risks of oligoasthenotertozoospermia (OAT) were found in most of the genetic models. In conclusion, this meta-analysis is in favor that the MTHFR C677T polymorphism is capable of causing male infertility susceptibility, especially in Asians and the subgroup of azoospermia.     

Family-based association study showing that immunoglobulin A nephropathy is associated with the polymorphisms 2093C and 2180T in the 3' untranslated region of the Megsin gene

Immunoglobulin A nephropathy (IgAN) is considered to be a multifactorial disease with genetic and environmental factors contributing to its pathogenesis. The genes involved in susceptibility and progression of the disease have not yet been clearly elucidated. Megsin (SERPINB7) is an important candidate gene, predominantly expressed in glomerular mesangium and upregulated in IgAN. To investigate the potential role of this and other genes in IgAN, patients with biopsy-proven IgAN were recruited, as were family members, for a family-based association study. The genotypes of the polymorphisms C2093T and C2180T within the 3' untranslated region of the gene were determined by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. The results were analyzed by transmission disequilibrium test (TDT) and haplotype relative risk (HRR). TDT analyses revealed that Megsin 2093C and 2180T alleles were significantly more transmitted from heterozygous parents to patients than expected (C2093T: 127 trios, P = 0.034, C2180T: 100 trios, P = 0.002). Extended TDT showed increased cotransmission of the 2093C and 2180T alleles (232 families, P < 0.001). HRR revealed that the 2093C and 2180T alleles were more often transmitted to patients (P = 0.014, <0.001, respectively). Genetic variation in Megsin confers susceptibility to IgAN.     

Demonstration of secretory IgA in kidneys of patients with IgA nephropathy.

BACKGROUND: Recently we reported a possible role for secretory IgA (SIgA) in IgA nephropathy (IgAN), as suggested by increased serum levels in patients with active disease and accumulation of SIgA in a glomerular eluate. Therefore, we attempted to find support for these findings by analysis of the presence of SIgA in biopsies of IgAN patients. METHODS: Renal biopsies of 26 patients with biopsy-proven IgAN were analysed for the presence of SIgA and complement proteins. RESULTS: In 15% mesangial deposition of SIgA was demonstrated, using a specific staining for secretory component (SC) and colocalization with IgA. The presence of SIgA in these biopsies showed a strong correlation with deposition of mannose-binding lectin (MBL) and C4d. Moreover, we observed a strong colocalization between SIgA and MBL or C4d. This local complement activation has previously been linked to more severe renal disease. CONCLUSIONS: Therefore, these data provide additional evidence for a pathogenic role for SIgA in IgA nephropathy.     

Relationship between methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism and type 2 diabetic nephropathy risk: a meta-analysis

Relationship between methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism and type 2 diabetic nephropathy (T2DN) risk is still unclear. This study was performed to evaluate if there is an association between the MTHFR A1298C gene polymorphism and T2DN risk using meta-analysis. The relevant reports were searched and identified from PubMed, Cochrane Library on 1 October 2013, and eligible studies were included and synthesized. Eight reports were recruited into this meta-analysis for the association of the MTHFR A1298C gene polymorphism with T2DN risk. The MTHFR A1298C C allele or CC genotype was shown to be not associated with T2DN risk (C allele: OR?=?0.76, 95% CI: 0.43–1.34, p?=?0.34; CC genotype: OR?=?1.18, 95% CI: 0.63–2.22, p?=?0.60). Interestingly, AA genotype was associated with the T2DN risk (OR?=?0.68, 95% CI: 0.49–0.96, p?=?0.03). In the sensitivity analysis according to the Hardy–Weinberg equilibrium (HWE), the results were consistent with those in non-sensitivity analysis. However, in the sensitivity analysis according to the control source from hospital, sample size of case (≥100), sample size of case (<100), the MTHFR A1298C gene polymorphism was not associated with T2DN risk. In conclusion, the MTHFR A1298C gene polymorphism was not associated with T2DN risk. However, additional studies are required to firmly establish a correlation between the MTHFR A1298C gene polymorphism and T2DN risk.     

Association of IgA nephropathy with Clostridium difficile colitis

Immunoglobulin A (IgA) nephropathy, the most common cause of glomerulonephritis worldwide, is usually idiopathic in origin and renal limited. Secondary IgA nephropathy has been associated with systemic disease, including such gastrointestinal tract disturbances as celiac sprue and inflammatory bowel disease. We describe gross hematuria and reversible acute renal failure from IgA nephropathy in a patient with cephalosporin-induced Clostridium difficile colitis. In addition to mesangial IgA and C3 deposition, renal histological examination showed glomerular bleeding, intratubular red blood cell casts, and acute tubular necrosis. To the best of our knowledge, this is the first report of an association between IgA nephropathy and C difficile colitis.     

Association between the RAGE gene -374T/A, -429T/C polymorphisms and diabetic nephropathy: a meta-analysis

Abstract

Aim: The investigations into the association between the receptor for advanced glycation end products (RAGE) gene -374T/A, -429T/C polymorphisms and diabetic nephropathy (DN) in several case–control studies have rendered conflicting results. To shed light on these inconclusive findings, a meta-analysis of all the eligible studies relating these two polymorphisms to the risk of DN was conducted. Methods: The databases were searched for relevant articles up to July 2014. A pooled estimate of the genetic association, the heterogeneity between studies, and the publication bias were investigated. Results: Eight studies with 1725 cases and 1857 controls were enrolled in -374T/A polymorphism analysis. The main analysis indicated no association for the allele contrast, the recessive model and the dominant model. Subgroup analyses in Caucasians and in type 2 diabetes also showed no association between -374T/A polymorphism and DN. Five studies with 1019 cases and 792 controls were enrolled in -429T/C polymorphism analysis. The main analysis revealed heterogeneity and no association for the allele contrast and the dominant model. However, the recessive model for -429C allele diminished the heterogeneity and showed a marginal association overall [fixed-effects OR?=?2.83 (1.33–6.00) and random effects OR?=?2.50 (1.00–6.24), respectively]. Conclusions: Our meta-analysis indicated that the RAGE gene -429CC genotype might be a risk factor for DN in patients with type 2 diabetes.     

No association of the -2518 MCP-1 A/G promoter polymorphism with incidence and clinical course of IgA nephropathy.

BACKGROUND: The clinical course of IgA nephropathy is highly variable, ranging from complete remission to progression with end-stage renal disease. Although the mechanisms involved in disease progression are not characterized in detail, loss of renal function is positively correlated with mononuclear cell infiltration. In general, chemokines play an important role in the directional recruitment of inflammatory cells. Recently, a polymorphism in the distal 5' regulatory region of the chemokine monocyte chemoattractant protein-1 (MCP-1), which affects gene expression, has been described (A/G at position -2518). The aim of our study was to evaluate a possible association of this polymorphism with disease progression in patients with IgA nephropathy, as well as susceptibility to this form of glomerulonephritis. METHODS: Blood samples from 207 patients with biopsy proven IgA nephropathy and 140 ethnically, age and sex-matched healthy controls were collected and genomic DNA was extracted. MCP-1 -2518 genotype was assessed by PCR, followed by restriction fragment length polymorphism analysis. Genotype distribution between the two groups was compared by chi(2) test. Cumulative renal survival was assessed by Kaplan-Meier plot and log-rank analysis. RESULTS: 111 (53.6%) patients had the MCP-1 -2518 wild-type A/A, 83 (40.1%) were heterozygous for the G allele and 13 (6.3%) patients showed homozygosity. The allelic distribution was not significantly different in the control group of 140 healthy blood donors (P = 0.71). Renal survival analysis of patients did not reveal statistically significant differences in cumulative survival (P = 0.32), median survival time and 5 year survival rate between the wild-type group and carriers of the G allele. Furthermore, the number of infiltrating CD68-positive monocytes/macrophages into the kidneys of patients with IgA nephropathy was not statistically different between the groups. CONCLUSION: Our data indicate that no association exists between the -2518 A/G polymorphism and susceptibility to IgA nephropathy or its clinical course.     

IgA肾病患者C1GALT1C1基因的体细胞突变筛查

目的 探讨IgA肾病（IgAN）患者β1,3半乳糖转移酶的分子伴侣Cosme编码基因C1GALT1C1基因体细胞突变情况。方法 27例IgA肾病患者及19例正常健康对照作为研究对象。提取研究对象外周血基因组DNA,扩增C1GALT1C1基因的编码区,采用PCR产物直接测序的方法进行突变筛查。然后,分离其中15例IgA肾病患者及7例健康男性对照的外周血B淋巴细胞,提取DNA。对C1GALT1C1基因编码区进行扩增,PCR产物进行克隆,各挑选平均8～10个克隆进行体细胞突变筛查。结果 46例个体全血基因组DNA的PCR扩增产物测序发现,2例患者及1例健康对照存在外显子T393A变异,次等位基因频率（MAF）为6．9%[SNP数据库（dbSNP）报告为9．5%]。B淋巴细胞DNA序列分析显示,在22例个体（15例IgA肾病患者,7例健康对照）送检的总共202个克隆中,未发现新的突变和多态性位点。结论 C1GALT1C1基因编码区T393A多态位点在本研究人群中为唯一发现的多态性位点,其次等位基因频率（MAF）较既往报道略低。本研究尚未发现IgA肾病患者B淋巴细胞存在体细胞突变。     

结缔组织生长因子基因启动子多态性与IgA肾病的关系

目的 研究结缔组织生长因子基因启动子多态性及其与上海地区中国人IgA肾病发生的相关性。方法 应用聚合酶链反应(PCR)-PCR产物直接测序技术，对50例IgA肾病(IgAN)患者和30例健康对照者(包括28例中国人和2例白种人)进行结缔组织生长因子基因ccn2(ctgf)启动子多态性研究。结果 检测到1种多态和1种突变。多态性改变G-447／C位于ccn2基因启动子的骨髓锌指蛋白(MZF)1结合基序附近。50例IgAN患者中有G．447／C多态性2例(4％)；28例中国健康对照者中有1例(3、57％)，该多态性频率两组间差异无显著性意义。在1例IgAN患者中发现ccn2基因1号外显子第20位核苷酸处存在G→T颠换，该突变接近ccn2基因mRNA的5’端帽式结构区，30例正常人中未发现这种突变。结论 (1)中国人群中有ccn2基因启动子多态性存在，ccn2基因启动子G-447／C多态性可能与IgAN发生无直接相关。(2)IgAN患者中存在ccn2基因1号外显子5’非编码区G→T颠换。经检索，该突变属首次报道。     

Polymorphisms in the promoter region and at codon 54 of the MBL2 gene are not associated with IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) occurs sporadically in unrelated individuals. Several different polymorphic genes have been investigated in recent years in order to demonstrate their possible association with IgAN. Three recent, different studies with conflicting conclusions have discussed the role of the mannose binding lectin (MBL), a serum lectin involved in natural immunity, in the IgAN pathogenesis by examination of MBL deposits in biopsies. In the present study we investigated several polymorphisms of the MBL gene located in the promoter region and in the first exon. METHODS: MBL polymorphism detection was performed in 22 Italian patients with familial IgA nephropathy and in 138 Italian patients with the sporadic form of the disease. The polymorphisms in the MBL2 promoter region and in the exon 1 were investigated, respectively, by direct sequencing and by amplification refractory mutation system-polymerase chain reaction on genomic DNA collected from peripheral blood. Seventy-four unrelated healthy subjects matched for ethnic origin were used as controls. RESULTS: Allelic and genotypic frequencies of the polymorphisms at position -550, -328, -221 and at codon 54 did not show any differences between patients and controls. Similar frequency distributions of these polymorphisms were also found in the subgroups of IgAN patients subdivided according to the clinical manifestations and the progression of the disease. CONCLUSIONS: This study indicates that the analysed polymorphisms of the MBL gene do not appear to be primarily involved in the susceptibility and severity of IgAN.     

Adiponectin gene polymorphisms and susceptibility to diabetic nephropathy: a meta-analysis

Adiponectin (ADIPOQ) plays an important role in the pathogenesis of diabetic nephropathy (DN) and previous studies regarding the association between ADIPOQ polymorphisms and DN risk reported conflicting results. To derive a more precise estimation of this association, we performed a meta-analysis to assess the association between four ADIPOQ polymorphisms [?11391G?>?A (rs17300539), ?11377C?>?G (rs266729), +45T?>?G (rs2241766), and +276G?>?T (rs1501299)] and risk for DN. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were pooled to assess the association between four aforementioned polymorphisms and susceptibility to DN. Based on the included criteria, we selected 13 articles, among which 7 studies (cases/controls: 2749/7585) for ?11391G?>?A, 8 studies for ?11377C?>?G (3074/3842), 9 studies for +45T?>?G (2654/7710), and 10 studies for +276G?>?T (2812/7821), respectively. Our meta-analysis indicated no evidence heterogeneity among the included studies; thus, the fixed-effects model was used. Overall, there was an association between ADIPOQ ?11391A allele with increased DN risk (OR?=?1.186, 95% CI: 1.051–1.338, p?=?0.006). Subgroup by ethnicity suggested significant association between +45T?>?G polymorphism and DN risk among Caucasians (OR?=?1.122, 95% CI: 1.007–1.250, p?=?0.038). Sensitivity analysis suggested exclusion of any single study did not materially alter the overall pooled ORs above. Future studies are needed to validate these findings.