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IgA nephropathy (IgAN) is a genetically complex multifactorial trait. Over the past decade, population-based genome-wide association studies (GWAS) have identified more than 30 IgAN risk loci, providing novel perspectives on both the epidemiology of the disease and its underlying molecular mechanisms. In addition, the association between IgAN and galactose-deficient IgA1 (Gd-IgA1) presented another avenue for genetic exploration due to the heritability of the elevated serum Gd-IgA1 levels. These endeavors also yielded and enabled refinement of polygenic risk scores, which may help identify specific groups of individuals at significantly increased risks, leading to stratifications of medical treatments. In this review, we aim to explore the existing evidence for genetic causation in IgAN. We summarize the state of genetic research in IgAN and how it has led to the reformulation of the new pathogenesis model and novel therapeutic targets., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

It has been reported that many people with psoriasis have been diagnosed with secondary IgA nephropathy (IgAN). However, the mechanisms behind the association between psoriasis and IgAN have not been well clarified. The connection between psoriasis and IgAN deserves deeper exploration. Mendelian randomization (MR) analysis would be employed to explore the link of causality between IgAN and psoriasis, psoriasis vulgaris, other and unspecified psoriasis, guttate psoriasis, and arthropathic psoriasis. Transcriptomic analyses were carried out against the Gene Expression Omnibus databases. We identified crosstalk genes through the analysis of Differentially expressed genes and weight gene co-expression network analysis. Functional annotations were enriched for these crosstalk genes. Subsequently, we established a protein-protein interaction network, and candidate genes would be discovered through the utilization of the MCODE and CytoHubba plug-in applications. Lastly, the predictive efficacy of these genes was examined via creating receiver operating characteristic curves. The MR analysis suggested that psoriasis vulgaris patients were at a higher risk for IgAN. [OR = 1.040, 95%CI (1.005,1.076), p = 0.026 < 0.05]. Additionally, arthropathic psoriasis may augment the incidence of IgAN [OR = 1.081, 95%CI (1.040-1.124), p < 0.01] in the European population. Through the analysis of DEGs and WGCNA, we identified 12 significant genes (NETO2, RRM2, SLAMF7, GBP1, KIF20A, CCL4, MMP1, IL1β, NDC80, CXCL9, C15orf48, GSTA3), which may be potential crosstalk genes between the two diseases. Then, the functional annotation results indicated that the crosstalk genes seemed primarily involved in immune and inflammatory responses. By establishing the PPI network, we further discovered that CXCL9, IL1β, CCL4, and MMP1 play a vital part in psoriasis and IgAN, and all have good diagnostic values. Our MR analysis provided evidence that genetic vulnerability to IgAN may be associated with an elevated risk of psoriasis vulgaris and arthropathic psoriasis respectively among Europeans. Doctors should be aware of these associations when patients with psoriasis present with renal dysfunction, especially those with psoriasis vulgaris and arthropathic psoriasis. Chronic inflammation, drug effects, and immunity may contribute to the generation and development of both diseases. IL1β, CXCL9, CCL4, and MMP1 may be core biomarkers for psoriasis and IgAN., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although many susceptibility loci for IgA nephropathy (IgAN) have been identified, they only account for 11.0% of the overall IgAN variance. We performed a large genome-wide meta-analysis of IgAN in Han Chinese with 3616 cases and 10 417 controls to identify additional genetic loci of IgAN. Considering that inflammatory bowel disease (IBD) and asthma might share an etiology of dysregulated mucosal immunity with IgAN, we performed cross-trait integrative analysis by leveraging functional annotations of relevant cell type and the pleiotropic information from IBD and asthma. Among 8 669 456 imputed variants, we identified a novel locus at 4p14 containing the long noncoding RNA LOC101060498. Cell type enrichment analysis based on annotations suggested that PMA-I-stimulated CD4 + CD25 - IL17 + Th17 cell was the most relevant cell type for IgAN, which highlights the essential role of Th17 pathway in the pathogenesis of IgAN. Furthermore, we identified six more novel loci associated with IgAN, which included three loci showing pleiotropic effects with IBD or asthma (2q35/PNKD, 6q25.2/SCAF8, and 22q11.21/UBE2L3) and three loci specific to IgAN (14q32.32/TRAF3, 16q22.2/TXNL4B, and 21q21.3/LINC00113) in the pleiotropic analysis. Our findings support the involvement of mucosal immunity, especially T cell immune response and IL-17 signal pathway, in the development of IgAN and shed light on further investigation of IgAN., (© 2024. Higher Education Press.)

Celiac disease, characterized as an autoimmune disorder, possesses the capacity to affect multiple organs and systems. Earlier research has indicated an increased risk of kidney diseases associated with celiac disease. However, the potential causal relationship between genetic susceptibility to celiac disease and the risk of kidney diseases remains uncertain. We conducted Mendelian randomization analysis using nonoverlapping European population data, examining the link between celiac disease and 10 kidney traits in whole-genome association studies. We employed the inverse variance-weighted method to enhance statistical robustness, and results' reliability was reinforced through rigorous sensitivity analysis. Mendelian randomization analysis revealed a genetic susceptibility of celiac disease to an increased risk of immunoglobulin A nephropathy (OR = 1.44; 95% confidence interval [CI] = 1.17-1.78; P = 5.7 × 10-4), chronic glomerulonephritis (OR = 1.15; 95% CI = 1.08-1.22; P = 2.58 × 10-5), and a decline in estimated glomerular filtration rate (beta = -0.001; P = 2.99 × 10-4). Additionally, a potential positive trend in the causal relationship between celiac disease and membranous nephropathy (OR = 1.37; 95% CI = 1.08-1.74; P = 0.01) was observed. Sensitivity analysis indicated the absence of pleiotropy. This study contributes novel evidence establishing a causal link between celiac disease and kidney traits, indicating a potential association between celiac disease and an elevated risk of kidney diseases. The findings provide fresh perspectives for advancing mechanistic and clinical research into kidney diseases associated with celiac disease., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: To evaluate the association between single-nucleotide polymorphisms in the 3' untranslated region of the DEFA5 gene and IgA nephropathy (IgAN) risk, the authors performed an association study in the Chinese Han population. Materials & methods: The authors recruited 426 IgAN patients and 498 controls. The MassARRAY platform (Agena Bioscience, Inc., CA, USA) was used to genotype single-nucleotide polymorphisms in DEFA5 . Odds ratios and 95% CIs were calculated through logistic regression analysis. Results: The authors observed that rs12716641 significantly reduced IgAN risk in the allele (odds ratio: 0.77; p = 0.026) and genotype (odds ratio: 0.75; p = 0.039) models. Stratification analysis revealed that several genotypes of rs12716641 played a protective role against IgAN. Conclusion: The authors' results revealed that single-nucleotide polymorphisms in the 3' untranslated region of DEFA5 were associated with IgAN risk.

Glomerular diseases (GNs) are responsible for approximately 20% of chronic kidney diseases. Glucocorticoid receptor gene ( NR3C1 ) single nucleotide polymorphisms (SNPs) are implicated in differences in predisposition to autoimmunity and steroid sensitivity. The aim of this study was to evaluate the frequency of the NR3C1 SNPs-rs6198, rs41423247 and rs17209237-in 72 IgA nephropathy (IgAN) and 38 membranous nephropathy (MN) patients compared to 175 healthy controls and to correlate the effectiveness of treatment in IgAN and MN groups defined as a reduction of proteinuria <1 g/24 h after 12 months of treatment. Real-time polymerase chain reactions and SNP array-based typing were used. We found significant rs41423247 association with MN ( p = 0.026); a significant association of rs17209237 with eGFR reduction after follow-up period in all patients with GNs ( p = 0.021) and with the degree of proteinuria after 1 year of therapy in all patients with a glomerulopathy ( p = 0.013) and IgAN ( p = 0.021); and in the same groups treated with steroids ( p = 0.021; p = 0.012). We also observed the association between rs41423247 and IgAN histopathologic findings ( p = 0.012). In conclusion, our results indicate that NR3C1 polymorphisms may influence treatment susceptibility and clinical outcome in IgAN and MN.

Background: Immunoglobulin A nephropathy (IgAN) is one of the most common primary forms of glomerulonephritis, while IgA vasculitis (IgAV) is the most common systemic vasculitis in children., Objective: Herein we aimed to uncover single nucleotide polymorphism (SNP) markers associated with these two related diseases by applying association tests and Sanger sequencing., Methods: Within the discovery stage, genomic DNA in blood samples from 101 enrolled patients were genotyped by the Korean Biobank Array. Association tests were performed with 397 Korean reference genomes. In the validation stage, 26 independent samples were genotyped by Sanger sequencing., Results: Four SNPs were identified (P < 5 × 10 -8 ) in the discovery stage. To determine whether the genotypes determined by SNP array were accurate, additional genotyping via Sanger sequencing was performed. As a result, only one SNP, rs9428555, was properly genotyped. In the validation stage, the minor allele (A > G) was found in as many as 15 out of 26 samples (minor allele frequency = 0.288), even though this minor allele is rare in East Asians (< 3%)., Conclusions: We found rs9428555 as a novel susceptible locus associated with the development of both IgAN and IgAV in Koreans. Though we cannot conclude rs9428555 is the unique susceptible locus of IgAN and IgAV, it is likely a good marker as the minor allele of this SNP occurred much more often in the patient group here versus within East Asians as a whole., (© 2021. The Genetics Society of Korea.)

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Although most IgAN cases are sporadic, few show a familial aggregation. However, the prevalence and prognosis of IgAN individuals with positive familial history (FH) of renal disorders remains uncertain. To address these issues, we conducted a longitudinal observational study on a single-institution cohort of patients with biopsy-proven IgAN., Methods: A total of 467 IgAN patients who underwent renal biopsy during 1994 to 2019 were ascertained to have positive- or negative-FH by history taking and were followed for an average of 8.9 years. We compared the clinical and pathological features of the two subgroups. The primary outcome, a composite of a hard endpoint (end-stage renal disease [ESRD]) and surrogate endpoint (a 50% or more reduction in the estimated glomerular filtration rate [eGFR] from baseline), was evaluated. To estimate the risk for progression to ESRD, a Cox proportional hazards analysis was performed for a subset of patients who underwent follow-up for > 2 years and had an eGFR > 30 mL/min/1.73 m 2 at baseline (n = 389; observation, 8.7 years)., Results: Positive-FH subtype accounted for 11.6% (n = 54) of all IgAN patients. At baseline, there were no significant differences between the positive- and negative-FH subgroups regarding age, sex, comorbid disease, MEST-C score, observation period, and therapeutic interventions. However, the eGFR value at baselines was significantly lower in the positive-FH subgroup than in the negative-FH subgroup (P < 0.01). On multivariate analysis, positive-FH emerged an independent determinant of poorer renal outcomes (odds ratio, 2.31; 95% confidence interval, 1.10-4.85; P = 0.03), after adjusting for confounding factors. eGFR at follow-up was significantly lower in the positive-FH subgroup than in the negative-FH subgroup after adjustment for age and observation period., Conclusions: Positive-FH was found in 11.6% of all IgAN patients, consistent with the incidence seen in previous literature. A significantly lower eGFR at baseline and last follow-up and unfavorable renal outcomes in the positive-FH subgroup suggest that certain genetic risk factors predisposing to renal failure may exist in a fraction of our IgAN cohort. (331 words).

Background and Objectives: IgA nephropathy is the most common form of primary GN worldwide. The evidence of geographic and ethnic differences, as well as familial aggregation of the disease, supports a strong genetic contribution to IgA nephropathy. Evidence for genetic factors in IgA nephropathy comes also from genome-wide association patient-control studies. However, few studies have systematically evaluated the contribution of coding variation in IgA nephropathy., Design, Setting, Participants, & Measurements: We performed a two-stage exome chip-based association study in 13,242 samples, including 3363 patients with IgA nephropathy and 9879 healthy controls of Han Chinese ancestry. Common variant functional annotation, gene-based low-frequency variants analysis, differential mRNA expression, and gene network integration were also explored., Results: We identified three non-HLA gene regions ( FBXL21 , CCR6 , and STAT3 ) and one HLA gene region ( GABBR1 ) with suggestive significance ( P meta <5×10 -5 ) in single-variant associations. These novel non-HLA variants were annotated as expression-associated single-nucleotide polymorphisms and were located in enhancer regions enriched in histone marks H3K4me1 in primary B cells. Gene-based low-frequency variants analysis suggests CFB as another potential susceptibility gene. Further combined expression and network integration suggested that the five novel susceptibility genes, TGFBI , CCR6 , STAT3 , GABBR1 , and CFB , were involved in IgA nephropathy., Conclusions: Five novel gene regions with suggestive significance for IgA nephropathy were identified and shed new light for further mechanism investigation., (Copyright © 2021 by the American Society of Nephrology.)

The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism has been inconsistently reported to be a risk factor for Childhood immunoglobulin A vasculitis (IgAV) nephritis. We comprehensively searched electronic databases as of Jan 2020. Nineteen studies with 1104 cases and 1589 controls were included. Sensitivity analyses based on different subgroups were performed. Further analyses were conducted for association of ACE polymorphism with disease severity and prognosis. Significant associations were found between ACE I/D polymorphism and childhood IgAV nephritis, with the strongest association in DD vs. II comparison (OR 1.72, 95% CI 1.21-2.46). Subgroup analyses generally showed significant results. Besides, ACE polymorphism was significantly associated with proteinuria (DD + DI vs. II: OR 2.22, 95% CI 1.14-4.33; DI + II vs. DD: OR 0.49, 95% CI 0.30-0.81) and worse prognosis (the strongest effect in DD + DI vs. II: OR 4.43, 95% CI 1.84-10.71) among children with IgAV nephritis. The ACE polymorphism seemed not to be associated with hematuria, hypertension, and renal pathology. This study suggested significant association of ACE gene polymorphism with the risk of IgAV nephritis in children. D allele in the ACE genotype could be a useful genetic marker to predict proteinuria and worse prognosis for childhood IgAV nephritis.

Background: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk., Methods: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny., Results: Identification of three novel loci (rs6427389 on 1q23.1 [ P =8.18×10 -9 , OR=1.132], rs6942325 on 6p25.3 [ P =1.62×10 -11 , OR=1.165], and rs2240335 on 1p36.13 [ P =5.10×10 -9 , OR=1.114]), implicates FCRL3 , DUSP22.IRF4 , and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4 , and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3 . Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA&#95;DRB1&#95;140&#95;32657458&#95;T, and AA&#95;DQA1&#95;34&#95;32717152) and two SNPs (rs9275464 and rs2295119)., Conclusions: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs.  These variants may explain susceptibility differences between Chinese and European populations., (Copyright © 2020 by the American Society of Nephrology.)

Tumor necrosis factor receptor associated periodic fever syndrome (TRAPS) is caused by heterozygote mutations in TNFRSF1A, characterized by recurrent inflammatory attacks. In this report, we described two patients with different heterozygote mutations in TNFRSF1A. Patient 1, a 15-year-old male, had suffered from recurrent fever attacks accompanied by abdominal pain, eye manifestations, and myalgia with increased acute phase reactants since the age of 6-month. He had been unsuccessfully treated with colchicine for having familial Mediterranean fever without an identifiable MEFV mutation since the age of 4-year. At the age of 15 years, he was diagnosed with immunoglobulin (Ig) A nephropathy due to massive proteinuria and renal biopsy findings. Next generation sequencing revealed NM&#95;001065.3: c.236C>T; p. (Thr79Met); T50M heterozygote mutation in TNFRFS1A. He was treated with methylprednisolone and cyclosporine for IgA nephropathy, thereafter with canakinumab for TRAPS. Patient 2, a 17-year-old female, had recurrent arthritis attacks accompanied by increased acute phase reactants for the last two months. She had neither fever attacks nor rashes or myalgia. Her physical examination was normal between attacks. Magnetic resonance imaging of both knees and ankles showed no signs of chronic arthritis. MEFV analyzes showed no mutation. Next generation sequencing revealed NM&#95;001065.3: c.362G>A; p.(Arg121Gln); R92Q heterozygote mutation in TNFRFS1A. Arthritis attacks were treated successfully with ibuprofen thereafter. In conclusion, we wish to emphasize the diversity of the clinical manifestations between these two patients with distinct sequence variants in TNFRSF1A. Moreover, we presented a rare manifestation of TRAPS, IgA nephropathy., Competing Interests: Declaration of competing interest Authors; Sibel Balci, Rabia Miray Kisla Ekinci, Engin Melek, Bahriye Atmis, and Mustafa Yilmaz declare that they have no conflicts of interest., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Our previous genome-wide association study has identified a suggestive association at rs11264799 within FCRL3 (Fc receptor-like 3) locus on 1q23.1 for IgA nephropathy (IgAN) in a Chinese Han population. This study aims to investigate the association of FCRL3 variants with the susceptibility, clinicopathological phenotypes and prognosis of IgAN. Eleven FCRL3 single-nucleotide polymorphisms (SNPs) were selected and analyzed in this two-stage case/control study with a total of 1750 IgAN cases and 2500 healthy controls in a Chinese Han population. Unconditional logistic regression models were used to estimate odds ratios and 95% confidence intervals (CIs) as implemented in the PLINK software. Luciferase assays were applied to detect the allelic effect of rs11264794 on gene expression regulation. We found that four SNPs (rs11264794, rs7865684, rs11264799, and rs6691569) were significantly associated with IgAN susceptibility after Bonferroni correction in the combined samples. Genotype/phenotype association analysis observed that two SNPs (rs11264794 and rs11264793) were associated with less disease severity. After adjusting for confounders, rs11264794 was independently correlated with renal outcome in IgAN patients (hazard ratio = 0.64, 95% CI = 0.43-0.97, p  = 0.033). In addition, the protective allele A of rs11264794 was significantly associated with higher FCRL3 gene expression. Furthermore, luciferase reporter gene assays demonstrated that the minor allele of rs11264794 obviously reduced the specific binding between miR-183-5p.1 and FCRL3 3'-untranslated region. Our results indicate that FCRL3 gene polymorphisms are associated with the development and progression of IgAN, and the rs11264794-A allele showed a protective role for IgAN.

The purpose of this study was to investigate the relationship between Lipoma preferred partner (LPP) gene polymorphisms and the risk of Immunoglobulin A nephropathy (IgAN) in the Chinese Han population. In this case-control study, we genotyped three single nucleotide polymorphisms (SNPs) of the LPP gene in 357 IgAN cases and 384 controls, using Agena Bioscience MassARRAY technology and assessed their association with IgAN using the χ 2 test and genetic model analysis. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess risk and were adjusted for age and gender by logistic regression. In the allele model, there were significant associations between LPP rs1064607 (OR = 1.24; 95% CI = 1.01-1.53; p = 0.041), rs3796283 (OR = 1.32; 95% CI = 1.08-1.63; p = 0.008), and rs2378456 (OR = 1.29; 95% CI = 1.05-1.59; p = 0.016), as well as an increased risk of IgAN. In the dominant model, the "G/C-C/C" genotypes of rs1064607 (p = 0.023), the "G/A-G/G" genotypes of rs3796283 (p = 0.0013) and the "G/C-C/C" genotypes of rs2378456 (p = 0.00052) were risk factors for IgAN. The results of the stratified analysis showed that rs3796283 and rs2378456 were connected with susceptibility to IgAN in different subgroups. Our data may provide new evidence to research the etiology of IgAN., (Copyright © 2019. Published by Elsevier B.V.)

Previous genome-wide association studies have discovered significant association at ITGAX-ITGAM on 16p11.2 for IgA nephropathy (IgAN). In this study, we performed a two-stage association study that enrolled 1700 IgAN cases and 2400 controls to further investigate the relationship of ITGAX and ITGAM gene polymorphisms with IgAN. Seven single-nucleotide polymorphisms (SNPs) were selected for genotyping in 1000 IgAN cases and 1000 healthy controls in the discovery stage, and the significant SNP was further validated in additional 700 IgAN cases and 1400 healthy controls. We found that four SNPs (rs11150619, rs11150614, rs7190997, and rs4597342) showed potential associations with IgAN susceptibility in the discovery stage, but only SNP rs11150619 was further genotyped in the validation stage after multiple testing. The results indicated that rs11150619 was significantly associated with IgAN in the combined samples (OR = 0.81, 95%CI = 0.71-0.91, and dominant P = 6.68 × 10 -4 ). Moreover, patients with TT genotype of rs11150619 exhibited increased estimated glomerular filtration rate levels and a reduced proportion of global sclerosis compared with those with TC and CC genotypes. Our results suggested that ITGAX and ITGAM gene polymorphisms were associated with IgAN in a Chinese Han population, and the rs11150619-T allele showed a potential protective role for IgAN.

Background: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Recent evidence suggests that genetic factors are related to the pathogenesis of IgAN. We conducted a genome-wide association study (GWAS) to identify novel genetic susceptibility loci for IgAN in a Korean population., Methods: We enrolled 188 biopsy-confirmed IgAN cases and 455 healthy controls for the discovery stage and explored associations between IgAN and single nucleotide polymorphisms (SNPs) using a customized DNA chip. The significant SNPs from the discovery samples were then selected for replication in an independent cohort with 310 biopsy-confirmed IgAN cases and 438 healthy controls., Results: In the first stage, two SNPs (rs10172700 in LOC105373592 and rs2296136 in ANKRD16) were selected for further association analysis in the next stage. In the replication cohort, rs2296136 in ANKRD16 was significantly associated with IgAN (odds ratio [OR] = 1.40, 95% confidence interval [CI] 0.99-1.98, p = 0.05 in log-additive model, OR = 1.55, 95% CI = 1.06--2.27, p = 0.02 in dominant model, and OR = 0.70, 95% CI = 0.17--2.84, p = 0.62 in recessive model). rs2296136 in ANKRD16 also showed a significant association with IgAN in the entire study population combining GWAS and replication study (p = 0.0045 in log-additive model, p = 0.0027 in dominant model, and p = 0.76 in recessive model)., Conclusions: The SNPs identified in the present study could be good candidate markers for predicting IgAN in Koreans, although further experimental validation is needed.

Background: Previous studies indicate that genetic factors play an important role in the pathogenesis of IgA nephropathy (IgAN). To evaluate the association between single nucleotide polymorphisms (SNPs) in the 3'-untranslated region (3'-UTR) of genes and IgAN risk, we performed a case-control study in a Chinese Han population., Materials: Twelve SNPs were selected and genotyped in 384 IgAN patients and 357 healthy controls. Odds ratio (OR) and 95% confidence intervals (CI) were calculated by logistic regression adjusted for age and gender. Multifactor dimensionality reduction (MDR) was used to analyze the interaction of SNP-SNP with IgAN risk., Results: Our study demonstrated that IL-16 rs859 (OR = 0.75, p = 0.040) and CYP19A1 rs4646 (OR = 2.58, p = 0.017) polymorphism were related to the risk of IgAN. In stratified analyses by gender, CYP19A1 rs4646 (OR = 2.96, p = 0.015) and BACH1 rs372883 (OR = 1.81, p = 0.038) polymorphisms conferred susceptibility to IgAN in males. Besides, rs372883 reduced IgAN risk in females (OR = 0.44, p = 0.042). We also found rs859 polymorphism was correlated with grade I-II (OR = 0.42, p = 0.028) in subgroup analysis of Lee's classification. Additionally, we found rs4646 polymorphism was correlated with serum creatinine (p = 0.035)., Conclusion: Our results suggested that the IL-16 rs859, CYP19A1 rs4646, and BACH1 rs372883 polymorphisms have potential roles in the genetic susceptibility to IgAN in Chinese Han population., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Background and Objectives: At least 20 susceptibility loci of IgA nephropathy have been identified by genome-wide association studies to date. Whether these loci were associated with disease progression is unclear., Design, Setting, Participants, & Measurements: We enrolled 613 adult patients with IgA nephropathy for a follow-up of ≥12 months. All 20 IgA nephropathy susceptibility loci were selected and their tag single nucleotide polymorphisms (SNPs) were genotyped. After strict quality control, 16 SNPs and 517 patients with IgA nephropathy were eligible for subsequent analysis. Progression was defined as ESKD or 50% decrease in eGFR. A stepwise Cox regression analysis of all SNPs on Akaike information criterion was performed to select the best model., Results: A four-SNP model, rs11150612 ( ITGAM-ITGAX ), rs7634389 ( ST6GAL1 ), rs2412971 ( HORMAD2 ), and rs2856717 ( HLA-DQ/DR ), was selected as the best predictive model. The genetic risk score calculated on the basis of the four SNPs was independently associated with disease progression before (hazard ratio [HR], 1.65; 95% confidence interval [95% CI], 1.29 to 2.12) and after adjustment by a recently reported clinical model (HR, 1.29; 95% CI, 1.03 to 1.62) or clinical-pathologic model (HR, 1.35; 95% CI, 1.03 to 1.77). Compared with low genetic risk, patients with middle genetic risk had a 2.12-fold (95% CI, 1.33 to 3.40) increase of progression risk, whereas patients with high genetic risk had 3.61-fold (95% CI, 2.00 to 6.52) progression risk increase. In addition, incorporation of genetic risk score could potentially increase discrimination of the clinical model (c-statistic increase from 0.83 to 0.86) or the clinical-pathologic model (c-statistic increase from 0.82 to 0.85) in predicting 5-year progression risk., Conclusions: The four-SNP genetic risk score was independently associated with IgA nephropathy progression and could enhance the performance of clinical and clinical-pathologic risk models., (Copyright © 2018 by the American Society of Nephrology.)

The association between a single-nucleotide polymorphism (SNP; -607A/C) in the promoter region of the IL-18 gene with IL-18 promoter transcription activity and the level of IL-18 protein production has been observed repeatedly. However, the association between the IL-18-607A/C (rs1946518) promoter polymorphism and IgA nephropathy (IgAN) in a Chinese Han population is still unclear. A total of 166 patients with renal biopsy-proven IgAN and 198 healthy controls were recruited for this study. The SNP was genotyped by the polymerase chain reaction and the high-resolution melting method. Clinical characteristics and pathology grading of patients with IgAN were recorded at the time of the kidney biopsy. There was a significant difference in the distribution between the AA genotype and the AC/CC genotype [P=0.007, OR (95% CI)=1.885 (1.183-3.003)]. However, no significant differences were observed between the rs1946518 SNP and quantitative traits (all P>0.05) or different pathology grades (Lee's grading system and tubular atrophy/interstitial fibrosis according to the Oxford classification) (P=0.769 and P=0.7) of the patients. We first demonstrated that the AA genotype of the IL-18-607A/C was associated with an increased susceptibility to IgAN in this population.

Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10-11) and C1GALT1C1 (rs5910940, P = 2.7 x 10-8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1 that encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer.

Background/aims: IgA nephropathy (IgAN) is a common form of primary glomerulonephritis worldwide. Previous studies indicated that IL-10 single nucleotide polymorphisms (SNP) play an important role in IgAN pathogenesis, but the results were controversy. This study aimed to investigate the association between IL-10 SNPs (rs1800872, rs1800871, and rs1800896) with IgAN in a Chinese Han population., Methods: We conducted a case-control study that included 351 patients with IgAN and 310 age-, gender- and ethnicity-matched healthy controls. Three promoter SNPs (rs1800872, rs1800871, and rs1800896) of IL-10 were genotyped by Sequenom MassARRAY. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the relationship with IgAN., Results: We found that the rs1800896 did not correlate with IgAN risk, whereas rs1800872 and rs1800871 were significantly associated with increased IgAN risk in all genetic models. The haplotype analysis indicated that the CCA haplotype was associated with increased IgAN risk (OR = 1.36; 95% CI = 1.05-1.75). Moreover, there were no associations between these SNPs and blood pressure or gender, whereas the rs1800896 variant was correlated with higher 24-hour urine protein in patients with IgAN., Conclusion: Taken together, these results suggest that IL-10 is a susceptibility gene in patients with IgAN., (© 2017 The Author(s)Published by S. Karger AG, Basel.)

Immunoglobulin A nephropathy (IgAN) is a common form of chronic glomerulonephritis with unknown pathogenesis. Accumulating evidences have shown the ethnic-specific association between certain human leukocyte antigen (HLA) alleles and IgAN susceptibility. This study was designed to explore the relationship between HLA-DQB1 alleles and disease susceptibility and clinical manifestations of patients with IgAN in southern Han Chinese. A PCR sequence-based typing technique was used to detect HLA-DQB1 alleles in 217 IgAN patients and 229 healthy subjects. Clinical data were collected from each patient at the time of renal biopsy. Twenty HLA-DQB1 alleles were detected in IgAN patients and healthy subjects. High frequency of HLA-DQB1* 060101 and low frequency of HLA-DQB1*030101 were observed in IgAN patients compared with healthy controls. Further stratification analysis revealed that the frequency of DQB1*060101 was significantly higher in patients with urine protein ≥ 1.0 g/24 h than in patients with urine protein < 1.0 g/24 h. In combination with our previous DRB1 results, we also analyzed the association of DRB1-DQB1 haplotypes with IgAN. We found that the frequency of haplotype DRB1*090102-DQB1*060101 was significantly higher [odds ratio (OR) = 4.409, Pc = 0.016], whereas that of HLA-DRB1*070101-DQB1*020101 was significantly lower (OR = 0.194, Pc = 0.016) compared with healthy controls. Our study indicated that HLA-DQB1*060101 alleles may be a potential predictor of high-risk IgAN susceptibility in Chinese Han population.

A recent genome-wide association study of IgA nephropathy (IgAN) identified 1q32, which contains multiple complement regulatory genes, including the complement factor H (CFH) gene and the complement factor H-related (CFHRs) genes, as an IgAN susceptibility locus. Abnormal complement activation caused by a mutation in CFHR5 was shown to cause CFHR5 nephropathy, which shares many characteristics with IgAN. To explore the genetic effect of variants in CFHR5 on IgAN susceptibility, we recruited 500 patients with IgAN and 576 healthy controls for genetic analysis. We sequenced all exons and their intronic flanking regions as well as the untranslated regions of CFHR5 and compared the frequencies of identified variants using the sequence kernel association test. We identified 32 variants in CFHR5, including 28 rare and four common variants. The distribution of rare variants in CFHR5 in patients with IgAN differed significantly from that in controls (P=0.002). Among the rare variants, in silico programs predicted nine as potential functional variants, which we then assessed in functional assays. Compared with wild-type CFHR5, three recombinant CFHR5 proteins, CFHR5-M (c.508G>A/p.Val170Met), CFHR5-S (c.533A>G/p.Asn178Ser), and CFHR5-D (c.822A>T/p.Glu274Asp), showed significantly higher C3b binding capacity (CFHR5-M: 109.67%±3.54%; P=0.02; CFHR5-S: 174.27%±9.78%; P<0.001; CFHR5-D: 127.25%±1.75%; P<0.001), whereas another recombinant CFHR5 (c.776T>A/p.Leu259Termination) showed less C3b binding (56.89%±0.57%; P<0.001). Our study found that rare variants in CFHR5 may contribute to the genetic susceptibility to IgAN, which suggests that CFHR5 is an IgAN susceptibility gene., (Copyright © 2016 by the American Society of Nephrology.)

We explored the relationship between rs1047763, a single-nucleotide polymorphism (SNP) of the C1GALT1 gene, and genetic susceptibility to immunoglobulin A nephropathy (IgAN) in Xinjiang Uyghur people. The study comprised 90 patients with IgAN and 90 normal controls recruited from Uyghur people. The distribution of the rs1047763 polymorphism of C1GALT1 in each group was determined by direct sequencing analysis. The gene type, gene frequency, allele type, and allele frequency were calculated by direct counting and the genotype was investigated using the Hardy-Weinberg equilibrium test. The SPSS17.0 software was used for data processing, and genotype and allele frequencies were compared using the χ2 test. In the IgAN group, the AA, AG, and GG genotype frequencies in the rs1047763 polymorphism of the C1GALT1 gene were 21.10, 47.80, and 31.10%, respectively, while AA, AG, and GG genotype frequencies in the control group were 17.8, 40.0, and 42.2%, respectively. There was no statistically significant difference between the two groups (P > 0.05). The rs1047763 SNP of the C1GALT1 gene probably has no correlation with genetic susceptibility to IgAN in Xinjiang Uyghur people.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, and its pathogenesis is influenced by both genetic and environmental factors. In this study, we evaluated 23 tag single-nucleotide polymorphisms (tSNPs) in 21 IgAN-associated genes, in 200 subjects with IgAN and 310 healthy gender- and age-matched unrelated control subjects with no history of renal disease or hypertension. Using the co-dominant model, we found that two genotypes of rs3803800 in TNFSF13 were associated with an increased risk of IgAN: "GA" (OR = 1.03, 95% CI = 0.71-1.51, p = 0.018) and "AA" (OR = 2.45, 95% CI = 1.29-4.65, p = 0.018). The "AA" genotype was also associated with an increased risk of IgAN in the recessive model (OR = 2.41, 95% CI = 1.30-4.46, p = 0.018), as was the genotype "AA" rs10488764 in FDX1 (OR = 1.88, 95% CI = 1.01-3.53, p = 0.048). Interestingly, we found that the allele "A" of rs3803800 in TNFSF13 is associated with a decreased risk of IgAN in females (OR = 0.43, 95% CI = 0.20-0.95, p = 0.009), but with an increased risk in males (OR = 1.78, 95% CI = 0.86-3.66, p = 0.009). Our findings, combined with previously reported results, suggest that TNFSF13 and FDX1 have potential roles in IgAN in the Han Chinese population. This information may be useful in the development of early prognostics for IgAN., (Copyright © 2015. Published by Elsevier Inc.)

Background: Previously, a large proportion of the genetic components predisposing individuals to IgA nephropathy (IgAN) have been unidentified. Familial IgAN is enriched with genetic variations predisposing individuals to the disease. Whole exome sequencing is an effective way to explore disease-causing genes and gene variants., Methods: We performed exome sequencing on the probands from each of ten IgAN families, and on one of the unaffected member from 7 of the families. Sanger sequencing, bioinformatics and co-segregation analysis were performed for all available family members to detect deleterious genetic variation. The relatedness of the families was tested by haplotype analyses., Results: Six deleterious variants in 4 genes were observed to be associated with IgA nephropathy by co-segregating with the disease phenotypes in study families. MYCT1 p.Asp22Glufs*34 was associated with IgAN by co-segregating with its phenotypes in families 2, 7, and 9; DEFA4 p.Ala8Pro, p.Ala8Val, c.172+1G>T co-segregated in families 1, 2, and 3; ZNF543 p.Pro226Ala co-segregated in families 3, 5, and 6 and CARD8 p.Val98Lysfs*26 co-segregated in families 7 and 8. Among these genes, MYCT1, CARD8 and ZNF543 are novel. Our haplotype analyses showed that families in which the same variation(s) were co-segregating with IgAN were unrelated, except for DEFA4. Of the families carrying DEFA4, families 2 and 3 were possibly related, but not family 1, indicating that common genes/variations in these families were not due to the same founder. Interfamilial sharing of different co-segregating genes was also observed, demonstrating the polygenic nature of this disease., Conclusions: We discovered 6 deleterious variants in 4 genes associated with familial IgAN. These genes are good candidate genes that appear to be causally related to IgAN and warrant further study., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: MicroRNA 146a (miR-146a) is a 19 to 23 nucleotide long, small non-coding RNA with gene regulatory functions that has influence on the pathogenesis of many diseases. A single nucleotide polymorphism (rs2910164 C>G) in pre-miR-146a is correlated with the expression of miR-146a. The aim of this study was to perform an association analysis of rs2910164 with IgA nephropathy in adult patients from a Chinese Han population., Methods: A total of 145 patients with renal biopsy-proved IgA nephropathy (IgAN) and 179 healthy controls were recruited to the current study. rs2910164 was genotyped by the polymerase chain reaction (PCR) and high-resolution melting methods (HRM). Clinical characteristics and pathology grading of patients with IgAN were recorded at the time of kidney biopsy., Result: There were significant differences among the population of patients grouped by different age of onset in a co-dominant model (CG vs. CC vs. GG) (p = 0.033) and a recessive model (CG+CC vs. GG) (p = 0.001). However, no significant difference was observed in the distribution of genotypes between cases and controls (p = 0.144). There was also no significant difference between rs2910164 and patient quantitative traits (all p > 0.003) or different pathology grading (Lee's grading system and tubular atrophy/interstitial fibrosis in the Oxford classification) (all p > 0.05)., Conclusions: There was no association of rs2910164 with susceptibility to IgAN in adults from a Chinese Han population. However, rs2910164 was correlated with the age of onset of IgAN in adult patients.

Complement activation has a role in the pathogenesis of IgA nephropathy, an autoimmune disease mediated by pathogenic immune complexes consisting of galactose-deficient IgA1 bound by antiglycan antibodies. Of three complement-activation pathways, the alternative and lectin pathways are involved in IgA nephropathy. IgA1 can activate both pathways in vitro, and pathway components are present in the mesangial immunodeposits, including properdin and factor H in the alternative pathway and mannan-binding lectin, mannan-binding lectin-associated serine proteases 1 and 2, and C4d in the lectin pathway. Genome-wide association studies identified deletion of complement factor H-related genes 1 and 3 as protective against the disease. Because the corresponding gene products compete with factor H in the regulation of the alternative pathway, it has been hypothesized that the absence of these genes could lead to more potent inhibition of complement by factor H. Complement activation can take place directly on IgA1-containing immune complexes in circulation and/or after their deposition in the mesangium. Notably, complement factors and their fragments may serve as biomarkers of IgA nephropathy in serum, urine, or renal tissue. A better understanding of the role of complement in IgA nephropathy may provide potential targets and rationale for development of complement-targeting therapy of the disease., (Copyright © 2015 by the American Society of Nephrology.)

Immunoglobulin A (IgA) nephropathy (IgAN) is a common form of primary glomerulonephritis characterized by diffuse glomerular mesangial IgA1 deposition leading to mesangial proliferation and chronic glomerular inflammation. Analyses of serum IgA1 from IgAN patients revealed abnormal galactosylation of the O-linked carbohydrate moieties of IgA that may result from altered activity in the core of 1 b1,3-galactosyltransferase (C1GalT1). To evaluate the association between C1GalT1 single nucleotide polymorphisms (SNPs) and IgAN, we performed a case-control study on cohorts from the Uyghur population in China. A total of 180 IgAN patients and 180 healthy controls were recruited for the study. We sequenced 5 SNPs, including SNP1 (rs9639031), SNP2 (-527A/G), SNP3 (rs1008898), SNP4 (rs5882115), and SNP5 (rs1047763) in the C1GalT1 gene in all eligible participants. The frequencies of the I allele and DI genotype of rs5882115 in IgAN patients were significantly higher than those in controls (P < 0.05). The frequency of haplotype GAGDA was significantly higher in patients than in controls (0.0719 vs 0.00, P = 0.024). Polymorphisms in the C1GALT1 gene were associated with genetic susceptibility to Uyghur IgAN.

This meta-analysis was conducted to assess the association of Megsin 2093C/T, 2180C/T, C25663G gene polymorphism with the risk of IgA nephropathy (IgAN). The association literatures were identified from PubMed, Embase, Cochrane Library and CBM-disc (China Biological Medicine Database) on 1 January 2014, and eligible reports were recruited and synthesized. Seven eligible reports were recruited into this meta-analysis for the association of Megsin 2093C/T, 2180C/T, C25663G gene polymorphism with IgAN risk. In this meta-analysis, the association of Megsin 2093C/T TT genotype with IgAN risk in Asians was found. Interestingly, Megsin C25663G G allele and GG genotype were associated with the risk of IgAN in Asian population. However, Megsin 2180C/T gene polymorphism was not associated with IgAN risk in Asians. In conclusion, Megsin 2093C/T TT genotype, and C25663G G allele and GG genotype were associated with the risk of IgAN in Asian population. However, more studies should be performed in the future to confirm this association.

IgA nephropathy (IgAN) is a complex syndrome with high genetic heterogeneity. More recently, a genome-wide association study (GWAS) from Southern Han population revealed that variants within 8p23.1, where the DEFA genes encoding a-defensins assembled, were associated with susceptibility to IgAN. To replicate the association and fine-map the genetic variants, a case-control genetic study from an independent Northern Han cohort was conducted. A total of 60 single-nucleotide polymorphisms in a region spanning 350 kb encompassing the DEFA genes cluster were analyzed in 2096 individuals. Copy number variations of DEFA1A3 within the loci were also checked for the independent association. Functional significance of the associated variants was further examined by the in silico method as well as by cis-acting expression quantitative trait loci analysis with mRNA. It showed that 17 out of 60 (28.3%) variants were associated with susceptibility to IgAN. Two independent signals with functional potentials were discovered (rs2738058, P=4.64 × 10(-5), odds ratio (OR)=0.76, 95% confidence interval (CI) 0.66-0.87 and rs9644778, P=4.78 × 10(-3), OR=1.21, 95% CI 1.06-1.39). Besides, marginally significant association of rs9644778 risk genotype with lower proportion of gross hematuria (CC+CA vs AA 35.2% vs 30.2%, P=0.073) was observed. In conclusion, DEFA gene polymorphisms have potentially pathogenic roles in IgAN, and the role of mucosal immunity in the pathogenesis of IgAN has to be emphasized.

Association of uteroglobin G38A gene polymorphism and IgA nephropathy (IgAN) risk is still not clear. This investigation was conducted to assess if there was an association between the uteroglobin G38A gene polymorphism and IgAN risk using meta-analysis. The relevant literatures were identified from PubMed, and Cochrane Library on 10 October 2013, and eligible studies were included and synthesized. Seven reports were recruited into this meta-analysis for the association of the uteroglobin G38A gene polymorphism with IgAN risk. In overall population, the A allele and AA genotype were not associated with IgAN risk. Furthermore, the GG genotype was also not associated with IgAN risk in overall population. Interestingly, the association of uteroglobin G38A gene polymorphism with IgAN risk was also not found in Asians and in Caucasians. In the sensitivity analysis, according to Hardy-Weinberg equilibrium test, according to the control source from healthy, the genotyping methods using PCR-RFLP, PCR-SSCP, no association of the uteroglobin G38A gene polymorphism with IgAN risk was found and the results were similar to those in non-sensitivity analysis. In conclusion, the uteroglobin G38A gene polymorphism was not associated with IgAN risk. However, additional studies are required to firmly establish a correlation between the uteroglobin G38A gene polymorphism and IgAN risk.

The association between plasminogen activator inhibitor-1 (PAI-1) 4 G/5 G gene polymorphism and immunoglobulin A nephropathy (IgAN) risk is still controversial. A meta-analysis was performed to evaluate the association between PAI-1 4 G/5 G gene polymorphism and IgAN susceptibility. A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic database. Four articles were identified for the analysis of association between PAI-1 4 G/5 G gene polymorphism and IgAN risk. 4 G allele was not associated with IgAN susceptibility in overall populations and in Asians. Furthermore, 4 G/4 G and 5 G/5 G genotype were not associated with IgAN for overall populations, Asians. In conclusion, PAI-1 4 G/5 G gene polymorphism was not associated with IgAN risk in overall populations and in Asians. However, more studies should be performed in the future.

Background: Micro-RNAs (miRNAs) play important roles in the regulation of immune response and inflammation. The purpose of this study was to investigate the association between three single nucleotide polymorphisms (SNPs) (mir-146a rs2910164, let-7a-2 rs1143770, miR-196a2 rs11614913) and susceptibility to and severity of childhood immunoglobulin A (IgA) nephropathy (IgAN)., Methods: We genotyped three miRNA SNPs in two independent Han Chinese populations composed of 158 patients and 265 controls (discovery set), and 246 patients and 446 controls (validation set), respectively., Results: We found that rs2910164 was significantly associated with IgAN in the discovery but not the validation set. Combined analysis revealed that rs2910164 CC and CG genotypes were associated with increased risk of IgAN compared with the GG genotype [adjusted odds ratios (OR) = 1.684, 95 % confidence interval (CI)1.190-2.384, P = 0.003; adjusted OR = 1.472, 95 % CI 1.079-2.007, P = 0.015, respectively). We also found that the frequency of the rs2910164 CC genotype was significantly higher in patients with Haas grade III-V than in those with Haas grade I-II for all study populations (P < 0.05). The expression of miR-146a in normal renal tissues with CC genotype was lower than in those with a G allele (P = 0.038)., Conclusions: These results indicated that rs2910164 may affect the susceptibility and severity of pediatric IgAN. Further studies are needed to validate these findings.

Background: FOS has been implicated in the progression of renal disease including IgAN. In this study, we investigated whether polymorphisms of FOS family genes [FOS, FOSB, FOS-like antigen 1 (FOSL1), and FOSL2] were associated with immunoglobulin A nephropathy (IgAN) and the clinical phenotypes of IgAN patients., Methods: We genotyped single nucleotide polymorphisms (SNPs) of FOS family genes (rs2239615 and rs7101 for FOS, rs12373539 and rs2282695 for FOSB, rs637571 for FOSL1, and rs925255 for FOSL2) using direct sequencing in 198 IgAN patients and 290 control subjects., Results: No SNPs were associated with IgAN; however, in the analysis of clinical phenotypes, we found that rs637571 of FOSL1 was associated with podocyte foot process effacement of IgAN in additive (CT vs. TT vs. CC, P = 0.0031, OR = 2.08, 95% CI = 1.27-3.40) and dominant models (CT/TT vs. CC, P = 0.0034, OR = 2.50, 95% CI = 1.35-4.64). The frequency of genotypes containing the T allele was increased in IgAN patients with podocyte foot process effacement, compared to those without podocyte foot process effacement., Conclusion: These results suggest that FOSL1 may be related to IgAN severity., (© 2014 Wiley Periodicals, Inc.)

Many existing studies have demonstrated that genetic variants in interleukin (IL) genes might have an impact on an individual's susceptibility to IgA nephropathy (IgAN); but individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the relationships between IL genetic variants and IgAN risk. We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and China BioMedicine (CBM) and China National Knowledge Infrastructure (CNKI) databases from inception through August 1, 2013. Meta-analysis was performed using the STATA 12.0 software. Seven case-control studies were included with a total of 1135 IgAN patients and 1603 healthy controls. Our meta-analysis results revealed that genetic variants in IL-1 and IL-1RN genes were associated with an increased risk of IgAN. However, similar associations were not observed in IL-6, IL-10, and IL-22R genes. Subgroup analysis by ethnicity suggested that there were significant associations between IL genetic variants and an increased risk of IgAN among both Asian and Caucasian populations. Meta-regression analyses showed that gene types may be a major source of heterogeneity. No publication bias was detected in this meta-analysis. The present meta-analysis suggests that IL genetic variants may contribute to the risk of IgAN, especially in IL-1 and IL-1RN genes.

The effect of genetic markers associated with IgA nephropathy on risk of disease in sub-phenotype and progression is uncertain. Data from 2096 Chinese patients were used to create both un-weighted (uw) and weighted (w) genetic risk score (GRS). The association between GRS with disease susceptibility and clinical parameters were assessed. All nine selected single nucleotide polymorphisms (SNPs) were associated with susceptibility to IgAN. uwGRS and wGRS showed a similar fit in disease associations. With every 1-unit increase in the uwGRS, the disease risk increased by approximately 20%; whereas every one standard deviation increase in the wGRS, disease risk increased by approximately 40% ~ 60%. Association between rs3803800 and serum IgA was replicated, and risk groups in GRSs were associated with increased IgA/IgA1 levels. uwGRS9 ≥ 16 was an independent predictor for end stage renal disease (ESRD) in IgAN, with a relative risk of 2.52 (p = 6.68 × 10(-3)). In conclusion, we observed that GRSs comprising nine SNPs identified in a GWAS of IgAN were strongly associated with susceptibility to IgAN. The high risk GRS9 group had a high risk of ESRD in follow-up.

Recent studies suggest that dysregulated innate immunity plays an important role in the pathogenesis of immunoglobulin A nephropathy (IgAN). The interleukin-20 subfamily and its receptor, interleukin-22 receptor alpha-1 (IL-22R1), were recently identified as immunomodulators in human diseases, acting as mediators of mucosal host defense. However, the potential role of IL-22R1 in the pathogenesis of IgAN has not been explored. In the current study, 194 patients with IgAN and 287 normal controls were genotyped for coding polymorphisms of the IL-22R1 gene and the association between the polymorphisms and IgAN was investigated. Local expression of IL-22R1 was examined in patients with IgAN and healthy controls using immunohistochemistry. Our case-control analysis showed that genotypes of rs3795299 were associated with childhood IgAN. Individuals with the CC genotype of rs3795299 had about 3-fold reduced risk of IgAN compared with those with the GG genotype in the codominant model (P=0.0028) and those with the genotypes containing the G allele (GG or GC) in the recessive model (P=0.002). After Bonferroni correction, the association between the rs3795299 CC genotype and reduced risk of developing IgAN remained significant. Furthermore, the renal expression of IL-22R1 was significantly higher in healthy controls compared with subjects with IgAN. Our data suggest that the CC genotype of rs3795299 polymorphism in the IL-22R1 gene is associated with the reduced risk of IgAN, and this genetic association was supported by the higher renal expression of IL-22R1 in healthy controls compared with patients with IgAN.

Background and Objective: The association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and end-stage renal disease (ESRD) risk in IgA nephropathy (IgAN) patients is still controversial. A meta-analysis was performed to evaluate the association between ACE I/D gene polymorphism and ESRD susceptibility in IgAN patients., Method: A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases., Results: Thirteen articles were identified for the analysis of the association between ACE I/D gene polymorphism and ESRD risk in IgAN patients. D allele and DD genotype were associated with ESRD susceptibility in IgAN patients for overall populations (p=0.01 and 0.003, respectively). In Asians, there was a markedly positive association between DD genotype and ESRD susceptibility (p=0.03). Furthermore, D allele and DD genotype were associated with ESRD susceptibility in Caucasians (p=0.02 and 0.03, respectively). However, II genotype might not play a protective role against ESRD onset for overall populations, Asians and Caucasians., Conclusion: DD homozygote is a significant genetic molecular marker for the onset of ESRD in IgAN patients.

Background: IgA nephropathy (IgAN) is a complex syndrome characterized by deposition of IgA and IgA containing immune complexes (ICs) composed of IgG and complement C3 proteins in the mesangial area of glomeruli. The low-affinity receptors for the Fc region of IgG (FcγRs) are involved in autoantibody/immune complex-induced organ injury as well as ICs clearance. The aim of the study was to associate multiple polymorphisms within FCGR gene locus with IgAN in a large Chinese cohort., Patients and Methods: 60 single nucleotide polymorphisms (SNPs) spanning a 400 kb range within FCGR gene locus were analyzed in 2100 DNA samples from patients with biopsy proven IgAN and healthy age- and sex-matched controls from the same population in Chinese., Results: Among the 60 SNPs investigated, 15 gene polymorphisms within FCGR gene locus (25%) were associated with susceptibility to IgAN. The most significantly associated SNPs within individual genes were FCGR2B rs12118043 (p = 8.74*10(-3), OR 0.76, 95% CI 0.62-0.93), and FCRLB rs4657093 (p = 2.28*10(-3), OR 0.77, 95% CI 0.65-0.91). Both conditional analysis and linkage disequilibrium analysis suggested they were independent signals associated with IgAN. Associations between FCGR2B rs12118043 and proteinuria (p = 3.65×10(-2)) as well as gross hematuria (p = 4.53×10(-2)), between FCRLB rs4657093 and levels of serum creatinine (p = 2.67×10(-2)) as well as eGFR (p = 5.41*10(-3)) were also observed. Electronic cis-expression quantative trait loci analysis supported their possible functional significance, with protective genotypes correlating lower gene expressions., Conclusion: Our data from genetic associations and expression associations revealed potentially pathogenic roles of Fc receptor gene polymorphisms in IgAN.

Recent genome-wide association studies (GWAS) have identified multiple susceptibility loci for immunoglobulin A nephropathy (IgAN), the most common form of glomerulonephritis, implicating independent defects in adaptive immunity (three loci on chromosome 6p21 in the MHC region), innate immunity (8p23 DEFA locus, 17p23 TNFSF13 locus, 22q12 HORMAD2 locus), and the alternative complement pathway (1q32 CFH/CFHR locus). In geospatial analysis of 85 populations, a genetic risk score based on the replicated GWAS loci is highest in Asians, intermediate in Europeans, and lowest in Africans, capturing the known difference in prevalence among world populations. The genetic risk score also uncovered a previously unsuspected increased prevalence of IgAN-attributable kidney failure in Northern Europe. The IgAN risk alleles have opposing effects on many immune-mediated diseases, suggesting that selection has contributed to variation in risk allele frequencies among different populations. Incorporating genetic, immunologic, and biochemical data, we present a multistep pathogenesis model that provides testable hypotheses for dissecting the mechanisms of disease.

IgA nephropathy is one of the most common glomerulonephritis throughout the world, which is thought to be the multifactorial complex diseases, with genetic and environmental factors contributing to this disease. The failure of replicating the single genes in previous association studies may be of that the gene-gene interaction might have more influence on the susceptibility of the complex diseases. In all, 31 single-nucleotide polymorphisms (SNPs) in 24 candidate genes (which were involved in the pathways implicated in the development or progression of IgAN) were selected to conduct a large case-control association study in 527 IgAN patients and 543 healthy controls. Traditional linear logistic regression analyses were used to detect single-locus associations in dominant, recessive and additive genetic models. Bonferroni correction was used to adjust the P-values for multiple testing. The gene-gene interaction effects of multiple SNPs were detected by multifactor-dimensionality reduction (MDR) method. After Bonferroni correction, no significant single-locus associations was observed between IgAN patients and controls (Pc>0.05). The MDR analysis showed a potential interaction of C1GALT1-330G/T (rs1008898) and IL5RA31+197A/G (rs340833) on the susceptibility of IgAN (P<0.001). Gene-gene interaction may have some influence on the susceptibility to IgA nephropathy. This finding proposed a potential gene-gene interactive model for future studies.

Background: IgA nephropathy (IgAN) is not generally considered a hereditary disease, even though extensive evidence suggests an undefined genetic influence. Linkage analysis identified a number of genome regions that could contain variations linked to IgAN., Methods: In this case-control association study, genes possibly involved in the development of IgAN were investigated. DNA samples from 460 North Italian patients with IgAN and 444 controls were collected. Candidate genes were selected based on their possible functional involvement (6 genes) or because of their location within linkage-identified genomic regions IGAN2 and IGAN3 (5 and 13 genes within chromosome 4q26-31 and 17q12-22, respectively). One hundred and ninety-two tag and functional single-nucleotide polymorphisms (SNPs) were typed with Veracode GoldenGate technology (Illumina)., Results: C1GALT1 showed an association with IgAN (rs1008898: P = 0.0019 and rs7790522: P = 0.0049). Associations were found when the population was stratified by gender (C1GALT1, CD300LG, GRN, ITGA2B, ITGB3 in males and C1GALT1, TRPC3, B4GALNT2 in females) and by age (TLR4, ITGB3 in patients aged <27 years). Furthermore, rs7873784 in TLR4 showed an association with proteinuria (G allele: P = 0.0091; GG genotype: P = 0.0077)., Conclusions: Age and gender are likely to evidence distinct immunological and inflammatory reactions leading to individual susceptibility to IgAN. Overall, a genetic predisposition to sporadic IgAN was found. We might hypothesize that C1GALT1 and TLR4 polymorphisms influence the risk to develop IgAN and proteinuria, respectively.

Background: IgA nephropathy is characterized by a high heterogeneity of clinical expression with 10-30% of patients progressing to end-stage renal failure. The gene of the FcαRI or CD89 presents a single-nucleotide polymorphism responsible for a proinflammatory phenotype of neutrophils in vitro and ex vivo. The aim of our study was to assess whether this CD89 polymorphism 844 A->G is (i) a marker of disease susceptibility and/or (ii) associated with a more severe prognosis., Methods: All patients diagnosed with IgA nephropathy and for whom DNA frozen sample was available were included in this European monocentric retrospective analysis and compared to a cohort of healthy volunteers. Allelic discrimination was performed by real-time quantitative polymerase chain reaction (Applied Biosystems™). We first compared the distribution of A and G alleles between patients and volunteers and then studied the relationships between alleles and renal survival, histological score, proteinuria and renal function at diagnosis., Results: Seven hundred and twenty-six patients were analyzed for the study of susceptibility and 425 in the association study. The presence of the G allele was not associated with the occurrence of IgA nephropathy (χ(2) test 0.57, ns). Likewise, renal survival and the criteria for disease activity at time of diagnosis were not affected by the presence of the G allele., Conclusions: No significant association between 844 A->G CD89 polymorphism and the expression of the IgA nephropathy in Caucasians exists. This result does, however, not preclude the implication of other CD89 polymorphisms neither the possibility for a role of CD89 in the pathogenesis of IgA nephropathy.

We performed a two-stage genome-wide association study of IgA nephropathy (IgAN) in Han Chinese, with 1,434 affected individuals (cases) and 4,270 controls in the discovery phase and follow-up of the top 61 SNPs in an additional 2,703 cases and 3,464 controls. We identified associations at 17p13 (rs3803800, P = 9.40 × 10(-11), OR = 1.21; rs4227, P = 4.31 × 10(-10), OR = 1.23) and 8p23 (rs2738048, P = 3.18 × 10(-14), OR = 0.79) that implicated the genes encoding tumor necrosis factor (TNFSF13) and α-defensin (DEFA) as susceptibility genes. In addition, we found multiple associations in the major histocompatibility complex (MHC) region (rs660895, P = 4.13 × 10(-20), OR = 1.34; rs1794275, P = 3.43 × 10(-13), OR = 1.30; rs2523946, P = 1.74 × 10(-11), OR = 1.21) and confirmed a previously reported association at 22q12 (rs12537, P = 1.17 × 10(-11), OR = 0.78). We also found that rs660895 was associated with clinical subtypes of IgAN (P = 0.003), proteinuria (P = 0.025) and IgA levels (P = 0.047). Our findings show that IgAN is associated with variants near genes involved in innate immunity and inflammation.

Background: and objective: The effect of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism on risk or progression of immunoglobulin A nephropathy (IgAN) is still debated.Therefore, a meta-analysis was performed to evaluate the association of ACE gene polymorphism with IgAN in different ethnic groups., Method: A predefined search strategy was performed to collect data from electronic databases., Results: Twenty articles were identified for the analysis of the relationship between ACE polymorphism and IgAN risk, including 11 in Asians and nine in Caucasians. There was a markedly positive association between the D allele or DD genotype and IgAN risk in Asians (OR = 1.27, p = 0.006; OR = 1.83, p < 0.0001). However, a link between D allele or DD genotype and IgAN risk was not found in Caucasians (OR = 1.04, p = 0.46; OR = 1.13, p = 0.12). Ten investigations were included for analysis of the association of ACE polymorphism with IgAN progression, including six in Asians and four in Caucasians. These data did not support a link between the ACE D allele or DD genotype and IgAN progression in Asians and Caucasians (Asians: D: OR = 1.03, p = 0.80; DD: OR = 1.43, p = 0.16; Caucasians: D: OR = 1.29, p = 0.22; DD: OR = 1.31, p = 0.17)., Conclusions: The D allele or DD genotype is associated with IgAN risk in Asian, but not in Caucasian populations; there was no significant association between the D allele or DD gene and IgAN progression for Asians and Caucasians.

Toll-like receptors (TLRs) are innate immune mediators that stimulate nuclear factor kappa B and the inflammatory cytokines. TLR1 is expressed in renal tubular epithelial cells when the kidney is injured, but the role of TLR1 gene in glomerulonephritis has not been clearly elucidated. We aimed to investigate the association of TLR1 polymorphisms with immunoglobulin A nephropathy (IgAN) in children. One hundred and ninety pediatric patients with biopsy-proven IgAN and 283 healthy control subjects were enrolled. Two single nucleotide polymorphisms of TLR1 gene [rs4833095 (missense, Asn248Ser) and rs5743557 (promoter, -414C/T)] were selected and genotyped by direct sequencing. For rs4833095, the C/T genotype in the codominant model (vs. the T/T genotype) [odds ratio (OR) = 2.11, 95% confidence interval (CI): 1.21-3.69, P = 0.009] and the genotype containing C allele (C/T and C/C) in the dominant model (vs. the T/T genotype) (OR = 1.97, 95% CI: 1.16-3.34, P = 0.012) were associated with an increased risk of IgAN. For rs5743557, the T/T genotype in the codominant model (vs. the C/C genotype) (OR = 1.74, 95% CI: 1.02-2.96, P = 0.041) appeared to be associated with IgAN risk. In haplotype analysis, the CT haplotype revealed an association with IgAN (codominant model, OR = 1.38, 95% CI: 1.06-1.80, P = 0.017; dominant model, OR = 1.76, 95% CI: 1.16-2.67, P = 0.008). After Bonferroni correction, the association of the genotypes of rs4833095 and the CT haplotype with IgAN risk remained significant. These findings suggest that TLR1 gene polymorphisms may affect IgAN susceptibility in Korean children., (© 2010 Blackwell Publishing Ltd.)

Neurotrophins (NTs) and their receptors (NTRs) are known to be important for pathogenesis of various inflammatory diseases that occur in not only neuronal but also nonneuronal tissues, including kidney. Here, we investigated association between childhood IgA nephropathy (IgAN) and single nucleotide polymorphisms (SNPs) of genes encoding NTs [nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)] and NTRs [nerve growth factor receptor (NGFR) and neurotrophic tyrosine kinase receptor 1-3 (NTRK1-3)]. The genotyping data of 197 patients and 289 control subjects revealed significant association between NGF SNP rs11102930 and presence of IgAN. Patient subgroup analysis revealed that that the presence of nephrotic range proteinuria (>40 mg/m/h) was associated with rs6334 of NTRK1 and rs11030104, rs7103411, rs7103873, and rs6484320 of BDNF. Significant genotype differences were observed in podocyte foot process effacement for rs1187321 and rs1187323 of NTRK2. Furthermore, some SNPs showed significantly different genotype distribution between patients with or without pathologically advanced disease markers, specifically in rs6334 of NTRK1. Our results suggest that SNPs of NTs and NTRs are associated with susceptibility, pathological advancement, podocyte foot process effacement, and development of proteinuria in childhood IgAN.

Many studies have suggested that CXCL8 and CXCR2 play an important role in the pathogenesis of several types of renal diseases. However, there is no prior study on the association between polymorphisms of these genes and IgA nephropathy (IgAN), especially in children. The genotyping data from 192 patients with childhood IgAN and 397 controls showed significant differences in the frequencies of the CXCL8 gene with rs2227306 (dominant, P = 0.019; overdominant, P = 0.009), rs2227543 (dominant, P = 0.01; overdominant, P = 0.0057), and rs4073 (codominant, P = 0.034; dominant, P = 0.011; overdominant, P = 0.022). In addition, 2 single-nucleotide polymorphism frequencies of the CXCR2 gene (rs4674257 and rs4674259) significantly differed between the patients with pathologically mild and patients with advanced disease. Further, 5 single-nucleotide polymorphisms of the CXCL8 and CXCR2 genes significantly differed in the patients with infiltration of inflammatory cells on the renal biopsy samples. The results of this study suggest that polymorphisms of CXCL8 are associated with increased susceptibility to IgAN, and polymorphisms of CXCR2 with the pathological progression of childhood IgAN. These genetic variations might provide insight into novel individualized antichemokine regimens for treatment.

Previous studies have suggested that insulin-like growth factor-1 (IGF-1) signaling might play an important role in renal fibrosis and regulation of the proliferation of mesangial cells and podocytes. We conducted the present study to investigate association between single nucleotide polymorphisms (SNPs) of IGF-1 (IGF-1) and IGF-1 receptor (IGF-1R) genes and childhood immunoglobulin (Ig) A nephropathy (IgAN). We analyzed five SNPs of IGF-1 and IGF-1R in 188 pediatric IgAN patients and in 263 healthy controls. We compared variations in SNPs in several sets of IgAN subgroups that were designated based on the presence of nephrotic range proteinuria (>40 mg/m2 per h), podocyte foot process effacement, and pathological progression. Genotyping of IgAN patients and controls revealed differences in IGF-1R rs2229765. Moreover, the rs2195239, rs978458, and rs1520220 SNPs of IGF-1 showed significant association with pathological progression. Thus, in the present study, we observed associations between the IGF-1/1R pathway, susceptibility to IgAN, and the pathologic progression of IgAN.