Genetic Complexities of the HLA Region and Idiopathic Membranous Nephropathy.
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SUBMITTER: Mladkova N
PROVIDER: S-EPMC5407745 | biostudies-literature | 2017 May
REPOSITORIES: biostudies-literature
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Genetic Complexities of the HLA Region and Idiopathic Membranous Nephropathy.
Mladkova Nikol N Kiryluk Krzysztof K
Journal of the American Society of Nephrology : JASN 20170410 5
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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.
| S-EPMC3913240 | biostudies-literature
Project description:BackgroundIdiopathic membranous nephropathy (IMN) is an autoimmune disease and the leading cause of adult nephritic syndrome. HLA-DQA1 had been identified to be associated with IMN in Europeans and the result was replicated in Chinese Han population. In this study, six single nucleotide polymorphisms (SNPs) in the promoter of HLA-DQA1 and other two SNPs with IgA nephropathy were included for the association analysis.MethodsThe SNPs were genotyped in 509 patients and 601 controls by the MassArray iPLEX. The quantification of anti-phospholipase A2 receptor (PLA2R) antibodies in sera of IMN patients was performed by anti-PLA2R ELISA (IgG) kit.ResultsAfter analysis, four SNPs were significantly associated with IMN, with rs2187668 and rs28383345 as the top two signals (P = 8.42×10-5 and 2.48×10-5, respectively). Even under dominant model, the two SNPs were still significantly associated with IMN (P = 3.50×10-3 for rs28383345 and P = 6.55×10-5 for rs2187668). After conditional study with rs2187668, rs28383345 was the only variant significantly correlated with IMN after Bonferroni correction (P = 0.016). The minor alleles of the two SNPs were also mutually exclusive in our cohort. This indicated that the two SNPs were independently associated with IMN in Chinese Han population. Levels of anti-PLA2R autoantibodies were correlated with the genotypes of the two SNPs, but not significantly (P>0.05).ConclusionsOur results revealed that a novel independent variant in the promoter of HLA-DQA1 was associated with IMN in Chinese Han population. The locus possessed regulatory role according to the data of RegulomeDB. The exact role of the SNPs on the expression of HLA-DQA1 needs further investigation.
| S-EPMC5520554 | biostudies-literature
Project description:Idiopathic membranous nephropathy (MN) is one common cause of idiopathic nephrotic syndrome in adults; 25% of MN patients proceed to end-stage renal disease. In adults, membranous nephropathy is a lead cause of nephrotic syndrome, with about 75% of the cases idiopathic. Secondary causes include autoimmune disease, infection, drugs and malignancy. Three hypotheses about pathogenesis have surfaced: preformed immune complex, in situ immune complex formation, and auto-antibody against podocyte membrane antigen. Pathogenesis does involve immune complex formation with later deposition in sub-epithelial sites, but definite mechanism is still unknown. Several genes were recently proven associated with primary membranous nephropathy in Taiwan: IL-6, NPHS1, TLR-4, TLR-9, STAT4, and MYH9 . These may provide a useful tool for diagnosis and prognosis. This article reviews epidemiology and lends new information on KIRREL2 (rs443186 and rs447707) polymorphisms as underlying causes of MN; polymorphisms revealed by this study warrant further investigation.
| S-EPMC4265015 | biostudies-literature
Project description:Overlapping idiopathic membranous nephropathy (IMN) and immunoglobulin A nephropathy (IgAN) is rare. This study aims to investigate the unique prognostic, clinical, and renal histopathological characteristics of IMN+IgAN. This retrospective observational study included 73 consecutive cases of IMN+IgAN and 425 cases of IMN treated between September 2006 and November 2015. Prognostic and baseline clinical and histopathological data were compared between the two patient groups. Poor prognostic events included a permanent 50% reduction in eGFR, end-stage renal disease, and all-cause mortality. Renal histopathology demonstrated that the patients with IMN+IgAN presented with significantly increased mesangial cell proliferation and matrix expansion, increased inflammatory cell infiltration, and higher proportions of arteriole hyalinosis and lesions than the patients with IMN (all P < 0.05). Kaplan-Meier analysis showed that the patients with IMN+IgAN had significantly higher cumulative incidence rates of partial or complete remission (PR or CR, P = 0.0085). Multivariate Cox model analysis revealed that old age at biopsy and high baseline serum creatinine and uric acid levels were significantly associated with poor prognosis (all P < 0.05), and increased IgA expression correlated significantly with PR or CR (P < 0.05). The present study found that overlapping IMN and IgAN presents with unique renal histopathology and appears not to cause a poorer prognosis than IMN.
| S-EPMC5597578 | biostudies-literature
Project description:BackgroundMembranous nephropathy (MN), a major cause of nephrotic syndrome, has attracted people's attention in recent years for its growing prevalence. It is the second or third leading cause of ESRD in patients with primary glomerulonephritis and is the leading glomerulopathy that recurs after kidney transplantation.SummaryMN can be classified as idiopathic membranous nephropathy (IMN) and secondary MN. The discovery of the M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) provides the new diagnostic methods and treatment strategies for IMN on the molecular level. The study on single nucleotide polymorphism of IMN genes, such as the single M-type phospholipase A2 receptor 1 (PLA2R1) gene and human leukocyte antigen (HLA) gene, explains the pathogenesis of the disease from the perspective of genetics and conforms to the trend of the era of precision medicine.Key messagesThis review focuses on advances in the pathogenesis of IMN, including molecular and genetic pathogenesis, as well as discussing the diagnostic and treatment guiding value brought by these new discoveries.
| S-EPMC7745661 | biostudies-literature
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.
2023-01-25 | GSE216841 | GEO
Project description:BackgroundBased on the etiology, membranous nephropathy (MN) can be categorized into idiopathic membranous nephropathy (IMN) and secondary membranous nephropathy. Malignancy-associated membranous nephropathy (MMN) is a common type of secondary MN. Its incidence is only second to that of lupus nephritis. As the treatment and prognosis of MMN differ significantly from those of other MNs, the identification of MMN is crucial for clinical practice. The purpose of this study was to develop a model that could efficiently discriminate MMN, to guide more precise selection of therapeutic strategies.MethodsA total of 385 with IMN and 62 patients with MMN, who were hospitalized at the First Affiliated Hospital of Zhengzhou University between January 2017 and December 2020 were included in this study. We constructed a discriminant model based on demographic information and laboratory parameters for distinguishing MMN and IMN. To avoid an increased false positivity rate resulting from the large difference in sample numbers between the two groups, we matched MMN and IMN in a 1:3 ratio according to gender. Regression analysis was subsequently performed and a discriminant model was constructed. The calibration ability and clinical utility of the model were assessed via calibration curve and decision curve analysis.ResultsWe constructed a discriminant model based on age, CD4+ T cell counts, levels of cystatin C, albumin, free triiodothyronine and body mass index, with a diagnostic power of 0.860 and 0.870 in the training and test groups, respectively. The model was validated to demonstrate good calibration capability and clinical utility.ConclusionIn clinical practice, patients demonstrating higher scores after screening with this model should be carefully monitored for the presence of tumors in order to improve their outcome.
| S-EPMC9329587 | biostudies-literature
Project description:BackgroundThe prevalence of idiopathic membranous nephropathy (IMN) is increasing worldwide and the gut microbiota is recognized to play a role in its pathology. The aim of this study was to understand the involvement of the gut-kidney axis in IMN by analyzing the composition of the gut microbiota of biopsy-proven IMN patients compared with healthy controls (HC).MethodsFecal samples from 30 patients with IMN diagnosed by renal biopsy and 30 healthy co-residents (control group) were collected for analysis in the Nephrology Department of the Second Affiliated Hospital of Harbin Medical University. The microbiota composition was analyzed by a 16S rRNA microbial profiling approach.ResultsThe results indicated that the α- and β-diversity of IMN patients differed significantly from those of the HC groups (P < 0.05). At the phylum level, IMN patients showed an increased abundance of Proteobacteria but a reduced abundance of Bacteroidota compared with the HC group. Actinobacteriota abundance showed a strong negative correlation with the estimated glomerular filtration rate. At the genus level, Faecalibacterium, Agathobacter, and Bacteroides were less abundant in the IMN group than in the HC group (LDA score > 2). Abundant bacterial functions related to lipid metabolism were observed among IMN group.ConclusionPatients with IMN appear to have an altered gut microbiome, which could provide reference for future research on the interaction mechanism between the intestinal flora and IMN.
| S-EPMC9055735 | biostudies-literature
Project description:Idiopathic membranous nephropathy (iMN) is a single-organ autoimmune disease characterized by subepithelial deposition of immune complexes containing IgG4 resulting in proteinuria, nephrotic syndrome, and, in some, end-stage renal disease. The pathogenesis involves a chronic IgG4 response against specific podocyte antigens which have now been at least partially defined in the neonatal, early childhood, and adult varieties. More has recently been learned about the genetic predisposition as well. This review discusses the pathophysiology of iMN in light of these discoveries and what is known about the genesis and potential clinical ramifications of an antigen specific IgG4 response.
| S-EPMC4928035 | biostudies-literature
Project description:ObjectiveNumerous studies have evaluated the association between the rs2187668 polymorphism in the human leucocyte antigen (HLA) complex class II HLA-DQ a-chain 1 (HLA-DQA1) gene and idiopathic membranous nephropathy (iMN) risk, which provided new insight into potential new targets for the treatment of iMN. However, this relationship remains inconclusive. Our aim was to evaluate the relationship between this polymorphism and iMN susceptibility by performing a meta-analysis.MethodsArticles were identified in the PubMed, Google Scholar, EMBASE, Cochran Library databases. Meta-analyses were performed for rs2187668 allele frequency, genotypes, and the association with iMN susceptibility. Subgroup analyses, publication bias and sensitivity analyses were also conducted.Results11 eligible studies (3209 cases and 7358 controls) from 7 articles were included. Statistical analyses were carried out using Stata 12.0, combining data from all the relevant studies. The pooled odds ratios (ORs) regarding the association between the HLA-DQA1 rs2187668 polymorphism and iMN risk were statistically significant [A vs G: OR = 3.34, 95% confidence interval (CI) = 2.70-4.13; AA vs GA + GG: OR = 8.69, 95% CI = 6.64-11.36; GG vs GA + AA: OR = 0.25, 95% CI = 0.19-0.33;AA vs GG: OR = 12.61, 95% CI = 8.02-19.81; GA vs GG: OR = 3.45, 95% CI = 2.79-4.25].ConclusionsOur pooled analysis showed a significant association between rs2187668-(A) allele and iMN susceptibility, and the intervention of this mutation might bring new therapeutic strategy for iMN. However, further studies should be performed to confirm this finding.
| S-EPMC6221752 | biostudies-literature