Influence of cytokine gene polymorphisms on IgA nephropathy

Aims. Recently, polymorphisms of cytokine genes have been associated with altered gene expression and modified cytokine production. We evaluated the impact of TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms on the clinical manifestations of IgA nephropathy. Patients and methods. The clinical course of 127 patients with biopsy-proven IgA nephropathy followed up for 6.6 +/- 6.0 years was studied. Patients were classified according to the slope of reciprocal serum creatinine into group A (slow progressors, n = 78) and group B (fast progressors, n = 49). TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A and IL-6 gene G-174C polymorphisms were determined by PCR amplification followed by restriction digestion with the endonucleases Sau96 I, Nco I, and Lwe I respectively. Results. The genotype distribution of the investigated polymorphisms was similar in patients and control subjects (ns). Age, initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes. The investigated polymorphisms were not associated with the progression of the IgA nephropathy, as shown by the similar genotype distribution in group A and group B (slow progressors: TGF-beta1, 92.3%; TNFalpha, 25.6%; IL-6, 74.4%; fast progressors: TGF-beta1, 85.7%; TNFalpha, 22.4%; IL-6: 81.6%, ns). Furthermore, these polymorphisms had no impact on renal survival in the Kaplan Meier analysis (ns). Conclusion. Our results suggest that TGF-beta1 gene Arg(25)-->Pro, TNFalpha gene G-308A, and IL-6 gene G-174C polymorphisms are not risk factors or markers of progression in Caucasian patients with IgA nephropathy.     

Role of TGF-beta1 in renal parenchymal scarring following childhood urinary tract infection.

BACKGROUND: Significant variability exists in the outcome of renal parenchymal inflammation following urinary tract infection (UTI) in childhood as some children experience renal parenchymal scarring (RPS) while others do not scar. Since TGF-beta1 is pro-fibrotic, we examined the role of this cytokine in RPS following UTI. METHODS: Five polymorphisms of the TGF-beta1 gene were investigated as well as the relationship between these polymorphisms and TGF-beta1 production by peripheral blood mononuclear cells (PBMC) in vitro. DNA was isolated from 91 children shown to have developed RPS, 43 children with no evidence of scarring (NS) following UTI, and 171 healthy controls. Genotyping was performed by restriction fragment length polymorphism (RFLP). PBMC were isolated from a subgroup of 24 patients from the total population. Cells were stimulated with LPS + PMA + PHA and then TGF-beta1 production was determined by ELISA. RESULTS: Comparing the NS with the RPS group, there was an increase in the -800 GA genotypes (18.6 vs. 7.4%, P=0.05; chi2) and the Leu10-->Pro CT (62.8 vs. 41.5%, P=0.021), and a decrease in the -509 TT genotype (0.0 vs. 8.5%, P=0.049). PBMC TGF-beta1 production was higher in those patients with the -800 GG compared to those with a GA genotype stimulation index [stimulated/unstimulated TGF-beta1 levels were 1.54 interquartile range (IQR) 1.42 to 1.75 vs. 1.19, IQR 0.94 to 1.51, P=0.031]. CONCLUSIONS: There is an association between the TGF-beta1 -800 GA, -509 TT and Leu10-->Pro CT genotypes and the presence or absence of RPS. The low TGF-beta1 producer status of the -800 GA genotype may protect against the development of a pro-fibrotic pathology.     

Association of C-509T and T869C polymorphisms of transforming growth factor-beta1 gene with chronic allograft nephropathy and graft survival in Korean renal transplant recipients

PURPOSE: Transforming growth factor-beta1 (TGF-beta1) has been associated with the promotion of renal allograft interstitial fibrosis and thereby chronic allograft nephropathy (CAN). The literature on TGF-beta1 polymorphisms and their importance in graft survival and CAN is not conclusive. METHODS: TGF-beta1 gene polymorphisms (C-509T and T869C) were examined in a group of 207 Korean renal transplant recipients using real-time polymerase chain reaction assays. The CAN group (n = 18) was defined by a typical biopsy confirming CAN or chronic calcineurin inhibitor nephrotoxicity. The rest of the patients were classified into the No CAN group (n = 189). RESULTS: No significant differences were observed in the genotype distributions of both C-509T and T869 polymorphisms between the two groups. Allele frequencies and age-, sex-, HLA mismatch-adjusted odds ratio of each genotype as assessed by logistic regression analysis were also not significantly different between the two groups. Linkage disequilibrium coefficients between polymorphisms indicated that investigated polymorphisms of TGF-beta1 (D' = 0.98) were in tight linkage. However, there were no significant differences in the frequencies of the reconstructed haplotypes between the two groups. Kaplan-Meier method and log-rank tests did not indicate any statistically significant effects of TGF-beta1 gene polymorphisms on graft survival. CONCLUSION: TGF-beta1 gene polymorphisms (C-509T, T869C) are not significantly associated with an increased risk of development of CAN and graft survival in Korean renal transplant recipients.     

The transforming growth factor-beta1 codon 10 gene polymorphism and accelerated graft vascular disease after clinical heart transplantation

BACKGROUND: The multifunctional cytokine transforming growth factor- (TGF) beta1 is thought to play a role in the pathogenesis of graft vascular disease (GVD). Polymorphisms at codon 10, (Leu10-->Pro) and codon 25 (Arg25-->Pro) in the signal sequence of the TGF-beta1 gene regulate the production and secretion of the protein. We investigated whether these polymorphisms are risk factors for the development of GVD after clinical heart transplantation. METHOD: TGF-beta1 polymorphisms, Leu10-->Pro and Arg25-->Pro, were determined in DNA from heart transplant recipients (n=252) and their donors (n=213), using sequence-specific oligonucleotide probing. GVD was angiographically diagnosed 1 year after transplantation. In addition other potential risk factors including underlying disease, recipient and donor age, recipient and donor gender, number of acute rejections in the first year, cold ischemia time, and HLA mismatches were analyzed by univariate and multivariate logistic regression analysis. RESULTS: Univariate analysis showed that the recipient TGF-beta1 polymorphism Leu10-->Pro, (P=0.056, chi2 test), underlying disease (P=0.01, chi2 test), number of acute rejections in the first-year (P=0.03, analysis of variance), and donor age (P<0.001, analysis of variance) were risk factors for the development of GVD. The TGF-beta1 Arg25-->Pro polymorphism was not a risk factor. Also in the multivariate analysis, the recipient TGF-beta1 codon 10 polymorphism was associated with GVD, with patients homozygous for Pro at greatest risk (odds ratio 7.7, P=0.03). Apart for the recipient TGF-beta1 Leu10-->Pro polymorphism, donor age appeared to be an independent risk factor for the development of GVD at 1 year. Patients with older donor hearts were at greater risk than patients receiving grafts from younger donors (odds ratio 1.1/year, P<0.001). CONCLUSION: Recipient TGF-beta1 Leu10-->Pro polymorphism and higher donor age are independent risk factors for the development of GVD after clinical heart transplantation.     

Renal failure after clinical heart transplantation is associated with the TGF-beta 1 codon 10 gene polymorphism.

BACKGROUND: To determine whether genetic factors are involved in the development of renal dysfunction due to cyclosporine nephrotoxicity, we analyzed 2 polymorphisms in the signal sequence of the transforming growth factor (TGF)-beta 1 gene; codon 10 (Leu(10) --> Pro) and codon 25 (Arg(25) --> Pro). METHOD: Using sequence specific oligonucleotide probing, we analyzed both TGF-beta1 gene polymorphisms in cardiac allograft recipients (n = 168) who survived at least 1 year with minimal follow-up of 7 years. Patients received cyclosporine and steroids as maintenance immunosuppressive therapy. Renal dysfunction was defined as a serum creatinine > or = 250 micromol/liter. RESULTS: Renal dysfunction was observed in 2% (3/168) of the patients at 1 year, in 7% (11/160) at 3 years, in 12% (18/152) at 5 years, and in 20% (26/131) at 7 years post-transplantation. The genotypic distributions for TGF-beta1 codon 10 were 7% Pro/Pro, 61% Pro/Leu, and 32% Leu/Leu, and for codon 25 these percentages were 1% Pro/Pro, 12% Pro/Arg, and 87% Arg/Arg. We found an association between the TGF-beta 1 genotype encoding proline at codon 10 and renal dysfunction. At 7 years post-transplantation, 26% (23/89) of the patients with the heterozygous Pro/Leu or homozygous Pro/Pro genotype had renal dysfunction vs only 7% (3/42) of the patients with the homozygous Leu/Leu genotype (p = 0.017). For the TGF-beta1 codon 25 genotypes, we found no association between TGF-beta 1 genotypes and renal dysfunction. CONCLUSION: Our data support the hypothesis that TGF-beta 1 is involved in the process leading to renal insufficiency in cyclosporine-treated cardiac allograft recipients. In these patients the presence of TGF-beta 1 Pro(10) might be a risk factor.     

No association of the TGF-beta1 gene polymorphisms with the renal progression in autosomal dominant polycystic kidney disease (ADPKD) patients

BACKGROUND: Two genetic loci, PKD I and PKD2, have been identified as being responsible for ADPKD, and PKD1 is known to be associated with a poor prognosis. However, the presence of an intrafamilial study clinical diversity suggests that there are disease-modifying loci. Because the mechanism ofthe renal failure in ADPKD includes a cystic growth and tubulointerstitial atrophy and fibrosis, we studied the associations between 2 polymorphisms in the TGF-beta1 gene, which are known to be associated with chronic tubulointerstitial inflammation, and ADPKD progression in Korean patients. PATIENTS AND METHODS: One hundred and twenty-five individuals who had ADPKD and 47 normal control subjects were genotyped by PCR-RFLP, the T869C (Leu10Pro) variant of TGF-beta gene leader sequence was discriminated with MspA1I and the G915C (Arg25Pro) variants with Bg1I. Statistical significances were determined using the Chi-square test. RESULTS: The distribution of the alleles for the TGF beta1 Leu10Pro polymorphism in ADPKD was: T 54%, C 46%, which was similar to the Korean (56: 44, p = 0.887) and Western controls (65: 35). In addition, no differences were found between the ESRD and the non-ESRD groups (p = 0.888) or the early hypertension and the normotension groups (p = 0.249). The distribution of alleles for the TGF beta1 Arg25Pro polymorphism showed only the GG type which was different from the Western population controls (G:C = 90:10, p = 0.000). CONCLUSIONS: Our results suggest that the polymorphism at Arg25Pro of TGF-beta1 in the Korean population has an allele distribution different from that ofthe Western population and that the polymorphism at Leu10Pro of TGF-beta1 has no association with the renal progression in Korean ADPKD patients.     

Association of TGF-beta1 polymorphisms with chronic renal disease

BACKGROUND: Transforming growth factor beta1 (TGF-beta1) plays an important role in tissue fibrosis and has been found to participate in cardiovascular disease (CVD). This study aimed to evaluate the association of TGF-beta1 polymorphisms with chronic renal disease (CRD), and its progression to dialysis in a retrospective longitudinal study of an end-stage renal disease (ESRD) cohort. METHODS: The Arg/Pro (codon 25) and Leu/Pro (codon 10) polymorphisms were genotyped in 104 ESRD patients aged 64 +/- 14 yrs (mean +/- SD), 62 males, and in 104 matched controls. RESULTS: The genotype distribution of Leu10Pro and Arg25Pro polymorphisms was different between patients and controls: Leu/Leu, Leu/Pro, Pro/Pro: 0.35, 0.50, 0.15 vs. 0.30, 0.24, 0.46 (p=0.001) and Arg/Arg, Arg/Pro, Pro/Pro: 0.79, 0.21, 0 vs. 0.87, 0.10, 0.03 (p=0.019). Similarly, haplotypes constructed with the combination of both polymorphisms were different among groups. There were no differences in CRD progression rate among genotypes. Codon 10 Leu allele was associated with the presence of clinical CVD in the ESRD patients (Leu/Leu, Leu/Pro, Pro/Pro: with CVD 0.49, 0.49, 0.02 vs. without CVD 0.27, 0.51, 0.22 (p=0.01). Combined polymorphism haplotypes were also significantly different between ESRD patients with and without CVD. This association was independent from other risk factors. CONCLUSIONS: TGF-beta1 polymorphisms are associated with ESRD, particularly in patients with associated clinical CVD, and could be useful as genetic markers of CRD and higher cardiovascular risk.     

TGF-beta1 gene polymorphisms in patients with end-stage heart failure.

BACKGROUND: The regulatory cytokine transforming growth factor (TGF)-beta1 is thought to play a role in atherosclerotic heart disease as well as in idiopathic cardiomyopathy. The production of TGF-beta1 is genetically controlled as polymorphisms in the signaling sequence of the TGF-beta1 gene leucine(10)-->proline and arginine(25)-->proline are involved in the regulation of the protein production level. We investigated whether these polymorphisms are associated with end-stage heart failure caused by dilated cardiomyopathy (CMP) or ischemic heart disease (IHD). METHODS: We determined polymorphisms using sequence specific oligonucleotide probing (SSOP) in genomic DNA samples from heart transplant recipients (n = 253) and controls (n = 94). Indications for transplantation were dilated CMP (n = 109) and IHD (n = 144). RESULTS: We found a difference in TGF-beta1 codon 10 genotype distribution among patients with IHD, dilated CMP, and controls (p = 0.034; chi(2) test). Patients with dilated CMP differed from patients with IHD (p = 0.044) and healthy controls (0.017). The genotype distribution between patients with IHD and controls was comparable. For codon 25, we found no difference in genotype distribution. CONCLUSIONS: The Leu(10)-->Pro (codon 10) polymorphism in the TGF-beta1 gene is associated with end-stage heart failure caused by dilated CMP and not with IHD. This observation suggests that TGF-beta1 is involved in the pathogenesis of CMP.     

Association of transforming growth factor-beta (TGF-beta) T869C (Leu 10Pro) gene polymorphisms with type 2 diabetic nephropathy in Chinese

INTRODUCTION: Transforming growth factor-beta (TGF-beta) is known to play a pivotal role in the regulation of extracellular matrix (ECM) accumulation. Since diabetic nephropathy (DMN) is characterized by basement membrane thickening and mesangial expansion, control of ECM deposition is believed to be important in the pathogenesis of the disease. Recently, TGF-beta T869C (Leu 10Pro) gene polymorphism has been identified which may be associated with circulating TGF-beta levels. METHODS: In order to examine the relationship between TGF-beta gene polymorphism with DMN in Chinese, we carried out a case-control study, which recruited 123 Chinese type 2 diabetic patients with an average duration of diabetes for 12 years. A total of 58 patients who developed DMN (micro- or macroalbuminuria, with or without renal impairment) were compared with 65 diabetic patients without DMN despite similar duration of disease (normoalbuminuric and creatinine <120 micromol/L). TGF-beta T869C (Leu 10Pro) gene polymorphism was determined by polymerase chain reaction (PCR). RESULTS: Both groups of patients had similar baseline characteristics, including blood pressure, diabetic control, and duration of diabetes. Distribution of TGF-beta T869C (Leu 10Pro) genotype among the whole group is confined to Hardy Weinberg equilibrium. The DMN+ group has higher frequency of TGF-beta CC/CT genotypes than the DMN- group [CC, CT, TT = (DMN+) 46, 45, 9 (%) vs. (DMN-) 37, 37, 26 (%), P < 0.05]. C allele frequency is also higher in the DMN+ group than DMN- group (69% vs. 55%, P < 0.05). The adjusted odds ratio for TGF-beta CC/CT vs. TT genotype to develop DMN is 3.8 (3.2 to 4.4). Multivariate logistic regression analysis [hypertension, gender, age, duration of diabetes, hemoglobin (HbA1c), usage of angiotensin-converting enzyme (ACE) inhibitor, and cholesterol level] showed that TGF-beta genotype (P = 0.03) is an independent predictor for type 2 DMN. Among patients with DMN, those with TGF-beta CC/CT genotypes also had worse renal function and increased risk for macroalbuminuria. CONCLUSION: Our results suggest that TGF-beta T869C (Leu 10Pro) gene polymorphism is associated with DMN in Chinese.     

Influence of cytokine gene polymorphisms on focal segmental glomerulosclerosis

BACKGROUND: Recently, polymorphisms of cytokine genes have been associated with modified gene expression and increased cytokine production. We evaluated the influence of TGF-beta(1) gene Arg(25)-->Pro, TNF alpha gene G-308A and IL-6 gene G-174C polymorphisms on the clinical manifestations of focal segmental glomerulosclerosis (FSGS). METHODS: The clinical course of 71 patients with biopsy-proven primary FSGS followed up for 6.0 +/- 4.4 years was studied. Patients were classified according to the slope of reciprocal serum creatinine into slow (n = 49) and fast (n = 22) progressors. One hundred healthy volunteers were analysed as controls. Genetic polymorphisms were determined by PCR amplification. RESULTS: The genotype distribution of the studied polymorphisms was similar in patients and controls (n.s.). Age, initial renal function, proteinuria and blood pressure did not differ significantly between patients with different genotypes (n.s.). The investigated polymorphisms were not associated with the progression of FSGS as shown by the similar genotype frequencies among slow and fast progressors (n.s.) and the renal survival in the Kaplan-Meier analysis (n.s.). CONCLUSION: Our results indicate that TGF-beta(1) gene Arg(25)-->Pro, TNF alpha gene G-308A and IL-6 gene G-174C polymorphisms are not risk factors or markers of progression in focal segmental glomerulosclerosis.     

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 MEGSIN 2093C-2180T haplotype at the 3' untranslated region with disease severity and progression of IgA nephropathy.

BACKGROUND: MEGSIN is a gene predominantly expressed in the renal mesangium, and is upregulated in IgA nephropathy (IgAN). Our previous study has shown that the 2093C and 2180T alleles at the 3' untranslated region (3'UTR) of the gene are associated with susceptibility to IgAN, but the relationships of these genetic variants with the clinical manifestations and renal histological lesions of IgAN have not been examined previously. METHODS: 302 IgAN patients followed up for 52.8+/-22.5 months were investigated. Haplotypes at the 3'UTR were constructed using the 2093C/T and 2180C/T alleles. The genotype-phenotype relationship was studied by correlations of haplotypes and the clinical data and renal histopathological changes. RESULTS: The 2093C-2180T haplotype was present more often in patients with disease that progressed more rapidly (chi2((C-T/others)) = 8.429, P = 0.004), and was also correlated with hypertension (chi2((C-T/others)) = 6.459, P = 0.012), severe proteinuria (>or=2 g/d) (chi2((C-T/others)) = 6.332, P = 0.013), and Lee's class IV and V histological changes (chi2((C-T/others)) = 9.640, P = 0.008). CONCLUSION: In this Chinese population, the 2093C-2180T haplotype at the 3'UTR of MEGSIN gene is associated with more severe forms of IgAN, and more rapid disease progression. This provides further evidence for the involvement of genetic variations of MEGSIN in the pathogenesis of IgAN.     

Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy

IgA nephropathy (IgAN) is a polygenic disorder and the precise role of genetic factors remains elusive. Increasing evidences have implicated the aberrant galactosylation of IgA1 molecules in the pathogenesis of IgAN. The galactosyltransferase, core 1 beta3-Gal-T, and its chaperone, Cosmc, play important roles in beta1,3 glycosylation of IgA1 molecule. A case-control association study was performed to investigate the association between single-nucleotide polymorphisms (SNPs) of C1GALT1 and C1GALT1C1 genes and the susceptibility to IgAN. A total of 1164 subjects were enrolled, including 670 IgAN patients and 494 geographically matched healthy controls. Five SNPs, -734C/T, -465A/G, -330G/T, -292C/-, and 1365G/A in C1GALT1 were selected as tagging SNPs. The D allele and DD genotype of -292C/- in IgAN patients were significantly lower than in the controls (P<0.01). The frequency of haplotype YATIG (Y=C or T) was significantly lower in patients than in controls (0.0719 vs 0.1168, P=2.775 x 10(-4), odds ratio (OR)=0.70). The haplotype YAGDA (0.1236 vs 0.0791, P=3.815 x 10(-3), OR=1.77) and YATDG (0.0840 vs 0.0298, P=1.258 x 10(-5), OR=3.03) were significantly higher in patients than in controls. The present study suggested that the polymorphisms of C1GALT1 gene were associated with the genetic susceptibility to IgAN in Chinese population.     

TGF-beta1 gene polymorphisms and peritoneal equilibration test results in CAPD patients

Transforming growth factor-beta1 (TGF-beta1) stimulates the expression of collagen mRNA in cultured human peritoneal mesangial cells, which may predispose them to developing peritoneal fibrosis. Polymorphisms in the signal sequence genetically may be responsible for increased TGF-beta1 production (i.e., a substitution at amino acid position 10 and 25, +869 Leu(10)-Pro and +915 Arg(25)-Pro, respectively). The aim of this study was to find out whether there is any relation between peritoneal equilibration test (PET) results and TGF-beta1 gene polymorphism. Thirty-two CAPD patients and 72 healthy subjects were included into the study. Each CAPD patient had undergone two PET with a two-year interval. The patients were classified according to the results of a baseline PET as high (high-high average) and low (low-low average) transporters. In high transporters group (n = 20), the genotype frequencies were found as 45% Leu/Leu, 55% Leu/Pro for codon 10; and 85% Arg/Arg, 15% Arg/Pro for codon 25. In low transporters group (n = 12), the genotype frequencies were detected as 66.7% Leu/Leu and 33.3% Leu/Pro for codon 10; and 83.3% Arg/Arg, 16.7% Arg/Pro for codon 25. The distribution of the TGF-beta1 genotypes in our control population was compatible with a Hardy-Weinberg equilibrium. We found no relation between TGF-beta1 genotypes and peritoneal transport group (chi(2) test, p > 0.5). There was no relation between TGF-beta1 genotype and longitudinal change in peritoneal transport. This study is the first study analyzing the possible link between TGF-betal gene polymorphisms and the characteristics of peritoneal transport and longitudinal change of peritoneal transport characteristics in CAPD patients. Further work is needed to clarify the functional importance of these two polymorphisms in TGF-beta1 production and in the development of peritoneal fibrosis.     

Association of interleukin-10 gene G-1082A polymorphism with the progression of primary glomerulonephritis

BACKGROUND: Interleukin-10 (IL-10) is a cytokine with immunosuppressive properties. We evaluated the influence of G-1082A polymorphism in the IL-10 gene promoter, which has been associated with modified IL-10 production, on the two most common forms of primary glomerulonephritis: IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS). METHODS: We studied Caucasian patients (N= 191) with biopsy-proven glomerulonephritis (IgAN: N= 123, FSGS: N= 68) followed-up for 6.5 +/- 5.5 years. Patients were classified according to the slope of reciprocal serum creatinine (>/= or <-0.1 dL(*)mg(-1) (*)year(-1)) into group A (slow progressors, IgAN: N= 75, FSGS: N= 47) and group B (fast progressors, IgAN: N= 48, FSGS: N= 21). One hundred healthy volunteers were analyzed as control patients. G-1082A polymorphism was determined by polymerase chain reaction (PCR) amplification. RESULTS: The allele frequencies were similar in patients and control group (NS). Initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes. G-1082A polymorphism was associated with the progression of both IgAN and FSGS: GA/AA genotypes were more frequent in group B (fast progressors) than in group A (slow progressors; P= 0.012 for IgAN, P < 0.05 for FSGS). Patients with the GA/AA genotypes showed a worse outcome in the Kaplan-Meier analysis of renal survival (P < 0.05 for both IgAN and FSGS). The IL-10 polymorphism remained an independent risk factor for progression in multivariate analysis (Cox regression model, P < 0.05 for IgAN and FSGS). CONCLUSION: Our results suggest that IL-10 gene G-1082A polymorphism is an important marker of progression in patients with IgAN and FSGS.     

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.     

Influence of Cytokine Gene Polymorphisms on IgA Nephropathy

Aims. Recently, polymorphisms of cytokine genes have been associated with altered gene expression and modified cytokine production. We evaluated the impact of TGF-β1 gene Arg²⁵→Pro, TNFα gene G-308A and IL-6 gene G-174C polymorphisms on the clinical manifestations of IgA nephropathy. Patients and methods. The clinical course of 127 patients with biopsy-proven IgA nephropathy followed up for 6.6 ± 6.0 years was studied. Patients were classified according to the slope of reciprocal serum creatinine into group A (slow progressors, n?=?78) and group B (fast progressors, n?=?49). TGF-β1 gene Arg²⁵→Pro, TNFα gene G-308A and IL-6 gene G-174C polymorphisms were determined by PCR amplification followed by restriction digestion with the endonucleases Sau96 I, Nco I, and Lwe I respectively. Results. The genotype distribution of the investigated polymorphisms was similar in patients and control subjects (ns). Age, initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes. The investigated polymorphisms were not associated with the progression of the IgA nephropathy, as shown by the similar genotype distribution in group A and group B (slow progressors: TGF-β1, 92.3%; TNFα, 25.6%; IL-6, 74.4%; fast progressors: TGF-β1, 85.7%; TNFα, 22.4%; IL-6: 81.6%, ns). Furthermore, these polymorphisms had no impact on renal survival in the Kaplan Meier analysis (ns). Conclusion. Our results suggest that TGF-β1 gene Arg²⁵→Pro, TNFα gene G-308A, and IL-6 gene G-174C polymorphisms are not risk factors or markers of progression in Caucasian patients with IgA nephropathy.     

Association of T869, C509T,G915C gene polymorphism of transforming growth factor-β1 with IgA nephropathy risk

This meta-analysis was conducted to assess the association of transforming growth factor-β1 (TGF-β1) T869C, C509T, G915C gene polymorphism with the risk of IgA nephropathy (IgAN). The association literatures were identified from PubMed, Cochrane Library up to October 1, 2013, and eligible reports were recruited and synthesized. Five reports were recruited into this meta-analysis for the association of TGF-β1 T869C, C509T, G915C gene polymorphism with IgAN risk. In this meta-analysis, the association of TGF-β1 T869C, C509T, G915C gene polymorphism with IgAN risk was not found. In conclusion, TGF-β1 T869C, C509T, G915C gene polymorphism is not associated with the IgAN risk. However, more studies should be performed in the future to confirm this association.