Dataset Information

TRPC6 single nucleotide polymorphisms and progression of idiopathic membranous nephropathy.

ABSTRACT:

Background

Activating mutations in the Transient Receptor Potential channel C6 (TRPC6) cause autosomal dominant focal segmental glomerular sclerosis (FSGS). TRPC6 expression is upregulated in renal biopsies of patients with idiopathic membranous glomerulopathy (iMN) and animal models thereof. In iMN, disease progression is characterized by glomerulosclerosis. In addition, a context-dependent TRPC6 overexpression was recently suggested in complement-mediated podocyte injury in e.g. iMN. Hence, we hypothesized that genetic variants in TRPC6 might affect susceptibility to development or progression of iMN.

Methods & results

Genomic DNA was isolated from blood samples of 101 iMN patients and 292 controls. By direct sequencing of the entire TRPC6 gene, 13 single nucleotide polymorphisms (SNPs) were identified in the iMN cohort, two of which were causing an amino acid substitution (rs3802829; Pro15Ser and rs36111323, Ala404Val). No statistically significant differences in genotypes or allele frequencies between patients and controls were observed. Clinical outcome in patients was determined (remission n?=?26, renal failure n?=?46, persistent proteinuria n?=?29, follow-up median 80 months {range 51-166}). The 13 identified SNPs showed no association with remission or renal failure. There were no differences in genotypes or allele frequencies between patients in remission and progressors.

Conclusions

Our data suggest that TRPC6 polymorphisms do not affect susceptibility to iMN, or clinical outcome in iMN.

SUBMITTER: Hofstra JM

PROVIDER: S-EPMC4096511 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

TRPC6 single nucleotide polymorphisms and progression of idiopathic membranous nephropathy.

Hofstra Julia M JM Coenen Marieke J H MJ Schijvenaars Mascha M V A P MM Berden Jo H M JH van der Vlag Johan J Hoefsloot Lies H LH Knoers Nine V A M NV Wetzels Jack F M JF Nijenhuis Tom T

PloS one 20140714 7

<h4>Background</h4>Activating mutations in the Transient Receptor Potential channel C6 (TRPC6) cause autosomal dominant focal segmental glomerular sclerosis (FSGS). TRPC6 expression is upregulated in renal biopsies of patients with idiopathic membranous glomerulopathy (iMN) and animal models thereof. In iMN, disease progression is characterized by glomerulosclerosis. In addition, a context-dependent TRPC6 overexpression was recently suggested in complement-mediated podocyte injury in e.g. iMN. H ...[more]

PMID: 25019165

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Project description:BACKGROUND AND OBJECTIVES: Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ ?-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study. Copy number variants (CNVs) within the Fc gamma receptor III (FCGR3) locus have been associated with several autoimmune diseases, but their role in IMN has not been studied. This study aimed to validate the association of HLA-DQA1 and PLA2R1 risk alleles with IMN in a Spanish cohort, test the putative association of FCGR3A and FCGR3B CNVs with IMN, and assess the use of these genetic factors to predict the clinical outcome of the disease. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: A Spanish cohort of 89 IMN patients and 286 matched controls without nephropathy was recruited between October of 2009 and July of 2012. Case-control studies for SNPs within HLA-DQA1 (rs2187668) and PLA2R1 (rs4664308) genes and CNVs for FCGR3A and FCGR3B genes were performed. The contribution of these polymorphisms to predict clinical outcome and renal function decline was analyzed. RESULTS: This study validated the association of these HLA-DQA1 and PLA2R1 SNPs with IMN in a Spanish cohort and its increased risk when combining both risk genotypes. No significant association was found between FCGR3 CNVs and IMN. These results revealed that HLA-DQA1 and PLA2R1 genotype combination adjusted for baseline proteinuria strongly predicted response to immunosuppressive therapy. HLA-DQA1 genotype adjusted for proteinuria was also linked with renal function decline. CONCLUSION: This study confirms that HLA-DQA1 and PLA2R1 genotypes are risk factors for IMN, whereas no association was identified for FCGR3 CNVs. This study provides, for the first time, evidence of the contribution of these HLA-DQA1 and PLA2R1 polymorphisms in predicting IMN response to immunosuppressors and disease progression. Future studies are needed to validate and identify prognostic markers.

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.

Project description:Idiopathic membranous nephropathy (IMN) is a major cause of nephrotic syndrome. No biomarker to predict the long-term prognosis of IMN is currently available. Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor-? superfamily and has been associated with chronic inflammatory disease. It has the potential to be a useful prognostic marker in patients with renal diseases, such as diabetic nephropathy and IgA nephropathy. This study examined whether GDF-15 is associated with the clinical parameters in IMN and showed that GDF-15 can predict IMN disease progression. A total of 35 patients with biopsy-proven IMN, treated at Chungnam National University Hospital from January 2010 to December 2015, were included. Patients younger than 18 years, those with secondary membranous nephropathy, and those lost to follow-up before 12 months were excluded. Levels of GDF-15 at the time of biopsy were measured using enzyme-linked immunosorbent assays. Disease progression was defined as a ?30% decline in estimated glomerular filtration rate (eGFR) or the development of end-stage renal disease. The mean follow-up was 44.1 months (range: 16-72 months). Using receiver operating curve analysis, the best serum GDF-15 cut-off value for predicting disease progression was 2.15?ng/ml (sensitivity: 75.0%, specificity: 82.1%, p = 0.007). GDF-15 was significantly related to age and initial renal function. In the Kaplan-Meier analysis, the risk of disease progression increased in patients with GDF-15???2.15?ng/ml when compared with those with GDF-15?<?2.15?ng/ml (50.0% versus 9.7%) (p = 0.012). In the multivariate Cox regression analysis adjusted for potential confounders, only GDF-15 was significantly associated with disease progression in IMN (p = 0.032). In conclusion, the GDF-15 level at the time of diagnosis has a significant negative correlation with initial renal function and is associated with a poor prognosis in IMN. Our results suggest that GDF-15 provides useful prognostic information in patients with IMN.

Dataset Information

TRPC6 single nucleotide polymorphisms and progression of idiopathic membranous nephropathy.

Background

Methods & results

Conclusions

Publications

TRPC6 single nucleotide polymorphisms and progression of idiopathic membranous nephropathy.

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