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Urokinase gene 3'-UTR T/C polymorphism is associated with malignancy and ESRD in idiopathic membranous nephropathy.

ABSTRACT: Idiopathic membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults, and 25% of MN patients proceed to ESRD. Urokinase plasminogen activator (uPA) may play an important role in reducing renal fibrosis. This study was conducted to clarify the relationship between uPA gene polymorphisms and clinical manifestations of MN. We recruited 91 biopsy-diagnosed MN patients and 105 healthy subjects. Genotyping of uPA gene 3'-UTR T/C polymorphism was performed by polymerase chain reaction methods. The genotype distribution had no effect on the development of MN. Thirteen patients (15.9%; P = 0.008) acquired malignancies and seventeen (20.7%; P = 0.006) patients progressed to ESRD with the C/C genotype, but no patients with the T/C genotype did. In conclusion, we demonstrated that the presence of the uPA gene 3'-UTR C/C genotype was associated with ESRD as well as acquired malignancies in MN patients. These findings should prompt specific considerations for the treatment of MN patients to maintain a balance between treating disease entities and protecting the immune system from cancers.

SUBMITTER: Chen CH

PROVIDER: S-EPMC4009112 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Urokinase gene 3'-UTR T/C polymorphism is associated with malignancy and ESRD in idiopathic membranous nephropathy.

Chen Cheng-Hsu CH Chen Shih-Yin SY Shu Kuo-Hsiung KH Wen Mei-Chin MC Cheng Chi-Hung CH Wu Ming-Ju MJ Yu Tung-Min TM Chuang Ya-Wen YW Tsai Fuu-Jen FJ

BioMed research international 20140414

Idiopathic membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome in adults, and 25% of MN patients proceed to ESRD. Urokinase plasminogen activator (uPA) may play an important role in reducing renal fibrosis. This study was conducted to clarify the relationship between uPA gene polymorphisms and clinical manifestations of MN. We recruited 91 biopsy-diagnosed MN patients and 105 healthy subjects. Genotyping of uPA gene 3'-UTR T/C polymorphism was performed by polymera ...[more]

PMID: 24822208

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Project description:BackgroundThe aim of this study was to investigate the correlation between the phospholipase A2 receptor (PLA2R) gene polymorphism and idiopathic membranous nephropathy (IMN) in Heilongjiang Chinese.MethodsThirty-five patients with IMN confirmed by renal biopsy attending the Heilongjiang Hospital of Traditional Chinese Medicine between June 2021 and December of 2021 were selected as the IMN group, and a group of 25 healthy participants from the Physical Examination Center of Heilongjiang Hospital of Traditional Chinese Medicine were enrolled as healthy controls. Polymerase chain reaction (PCR) was used to identify and genotype 8 single-nucleotide polymorphism (SNP) loci (rs16844715, rs2715918, rs2715928, rs35771982, rs3749119, rs3828323, rs4665143, and rs6757188) of PLA2R and to analyze the PLA2R gene polymorphisms that correlated with IMN. SPSS 26.0 statistical software was used for data analysis, and the chi-squared (χ2) goodness-of-fit test was used to determine whether each SNP genotype and allele in the PLA2R gene complied with the Hardy-Weinberg equilibrium. The qualitative data were analyzed via χ2 or Fisher exact probability method. Logistic regression was used to analyze risk factors, and the odds ratios (ORs) values and 95% confidence intervals (CIs) were calculated. α=0.05 was taken as the test level, and P<0.05 was considered statistically significant.ResultsStatistically significant differences were found in the genotype and allele frequencies of rs35771982 and rs3749119 between the IMN and control groups (P<0.05). Logistic regression analysis showed that the genotypes rs35771982 GG and rs3749119 CC were associated with IMN susceptibility. Statistically significant differences in uric acid level were found between the rs35771982 GG and CG + CC genotypes (P<0.05), while statistically significant differences in serum albumin were detected between rs3749119 CC and the CT + TT genotypes (P<0.05). Multivariate logistic regression analysis showed that gender, age, and triglyceride levels affected the occurrence of IMN (P<0.05).ConclusionsThe PLA2R gene polymorphisms rs35771982 and rs3749119 in Heilongjiang Chinese may be related to IMN susceptibility and correlated with clinical indicators of IMN. Gender, age, and triglyceride levels may influence the occurrence of IMN.

Project description:Membranous nephropathy (MN) is an autoimmune disease caused by binding of circulating antibodies to podocyte antigens in the kidney. For decades and still today primary MN has been considered to have an unspecified IgG4-driven autoimmune genesis, while secondary MN has been associated with other diseases, most notably cancer, and not linked to IgG4. Immunologic mechanisms of primary and malignancy-associated MN are assumed to be different, however, this has never been systematically evaluated. The identification of Phospholipase A2 Receptor 1 (PLA2R1) and Thrombospondin Type-1 Domain-Containing 7A (THSD7A) as target antigens in MN allows a pathogenesis-driven differential diagnosis. Recent data showing a molecular link between increased THSD7A-expression in tumors and THSD7A-antibody positive MN suggest a similar pathogenesis of malignancy-associated and primary MN. In order to better define the underlying immunologic processes, we systematically analyzed circulating antigen-specific IgG subclasses in the serum of 76 patients with PLA2R1-associated MN and 41 patients with THSD7A-associated MN in relationship to concurrent malignancy and disease outcome. Twenty-three patients in the study had malignancy-associated MN. We analyzed antigen-specific IgG subclasses in the serum of all patients at baseline and in 55 patients during follow-up by Western blot applying antigens derived from human kidney and lung. At baseline all 117 patients were positive for IgG4-antibodies against either PLA2R1 or THSD7A, while IgG3, IgG1, and IgG2-antibodies were found in 87, 72, and 26% of patients, respectively. There were no differences in the IgG subclass distribution between patients with primary vs. cancer-associated MN and no association with disease outcome. Moreover, levels of antigen-specific IgG4-antibodies were not different between primary and malignancy-associated MN and levels of all IgG subclasses did not differ between these groups. Both podocytes and lung bronchioles showed expression of both PLA2R1 and THSD7A when analyzed by immunofluorescence and Western blot. Every antigen-specific IgG subclass showed identical binding in both organs and autoantibodies bound the respective antigen only under non-reducing conditions. We conclude that antigen-specific IgG subclasses do not differentiate primary from malignancy-associated MN or predict disease prognosis. These data support the view that one common pathway may lead to primary and cancer-associated MN induced by PLA2R1- or THSD7A-antibodies.

Project description:Introduction: Minimal change disease (MCD) is a major cause of nephrotic syndrome. With a substantial number of patients requiring long-term immunosuppression leading to significant morbidity, the study aim was to determine MCD glomerular transcriptome to serve as a basis for biomarker discovery and novel drug target identification. Animal work showed podocyte injury induced by IL-7/IL-7R signaling (Zhai S, BBRC, 2018). Methods: Renal biopsies from adult patients representing the following groups were selected from the Norwegian Kidney Biopsy Registry: MCD (n=14), as well as normal tissue (n=8) and primary membranous nephropathy (MN; n=12) as the two reference groups. RNA for 75 base-pair paired-end RNASeq was obtained by dissecting glomeruli via laser capture microdissection (LCM) from FFPE cross-sections. Systematic delineation of condition-specific alteration in transcriptional landscapes was achieved by combining pathway-centered analyses with methodologies derived from network science and integrating multiple bioinformatics resources. Results: Compared to normal glomeruli, glomeuli from MCD displayed an inflammatory signature that appeared to be predominantly governed by the IL1 and IL7 systems. While enrichment of IL1 production and secretion was a shared feature of MCD and MN compared to normal tissue, responses involving IL7 pathway activation were unique to MCD. Indeed, IL7R expressed by glomeruli was the most up-regulated gene of to the interleukin-family in MCD vs normal controls. IL7 pathway activation was paralleled by significant enrichment in adaptive immune system processes and transcriptional regulation and depletion in pathways related to energy metabolism and transcription. Downregulation of these organ function-related themes again occurred predominately in MDC and were significantly less pronounced in MN. Conclusion: Our results demonstrate that archival FFPE-biopsies can be used to generate glomeruli-specific gene expression profiles suitable for systematic delineation of kidney-associated diseases. Here the latter provides a data-driven rationale to experimentally address these MCD-specific features as biomarkers and as novel drug targets. In this context inhibiting activation of the IL7 pathway may be particularly promising.

Dataset Information

Urokinase gene 3'-UTR T/C polymorphism is associated with malignancy and ESRD in idiopathic membranous nephropathy.

Publications

Urokinase gene 3'-UTR T/C polymorphism is associated with malignancy and ESRD in idiopathic membranous nephropathy.

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