Risk Of IgA Nephropathy Research Articles

Genetic variants of MCP-1 and CCR2 genes and IgA nephropathy risk.

Monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 stimulate inflammation response by activating and recruiting monocytes/macrophages. MCP-1 and CCR2 polymorphisms were reported to be associated with various diseases. To explore the relationship between MCP-1 and CCR2 polymorphisms and IgA nephropathy (IgAN), we conducted this case-control study by enrolling 351 IgAN patients and 310 health controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate potential associations of MCP-1 and CCR2 polymorphisms with susceptibility and clinical parameters of IgAN. No statistical differences between IgAN group and the control group in the MCP-1 -2518 and CCR2 +190 genotypic groups were observed (P > 0.05). Individuals with MCP-1 -2518 GG genotypes had a higher blood pressure (GG vs. AA+AG: OR = 1.79, 95% CI = 1.07-2.99, P = 0.026) and Lee's grade (GG vs. AA+AG: OR = 2.05, 95% CI = 1.19-3.54, P = 0.009; GG vs. AA: OR = 2.24, 95% CI = 1.19-4.20, P = 0.01), compared with patients with AA/AG genotypes. A significant association between CCR2 +190 polymorphism and Lee's grades was observed (GA+AA vs. GG: OR = 2.66, 95% CI = 1.63-4.35, P < 0.001; GA vs. AA+GG: OR = 2.27, 95% CI = 1.39-3.70, P = 0.001). Our results indicated that MCP-1 and CCR2 polymorphisms may influence the progression of IgAN, but not increase/decrease its susceptibility.

Fine Mapping Implicates a Deletion of CFHR1 and CFHR3 in Protection from IgA Nephropathy in Han Chinese.

An intronic variant at the complement factor H (CFH) gene on chromosome 1q32 (rs6677604) associates with risk of IgA nephropathy (IgAN), but the association signal has not been uniformly replicated in Han Chinese populations. We investigated whether the causal sequence variant resides in the CFH gene or the neighboring complement factor H-related 1 (CFHR1) gene and CFHR3, which harbor an 84-kb combined deletion (CFHR3,1Δ) in linkage disequilibrium with rs6677604. Imputation of 1000 Genomes Project data did not suggest new causal single-nucleotide variants within the CFH cluster. We next performed copy number analysis across the CFH locus in two independent Han Chinese case-control cohorts (combined n=3581). The CFHR3,1Δ and rs6677604-A alleles were rare (4.4% in patients and 7.1% in controls) and in strong linkage disequilibrium with each other (r2=0.95); of these alleles, CFHR3,1Δ associated more significantly with decreased risk of IgAN (odds ratio [OR], 0.56; 95% confidence interval [95% CI], 0.46 to 0.70; P=8.5 × 10-8 versus OR, 0.61; 95% CI, 0.50 to 0.75; P=1.6 × 10-6 for rs6677604-A). Moreover, CFHR3,1Δ explained all of the association signal at rs6677604 and remained significant after conditioning on rs6677604 genotype (P=0.01). Exploratory analyses of clinical and histopathologic parameters using the Oxford classification criteria revealed a suggestive association of CFHR3,1Δ with reduced tubulointerstitial injury (OR, 0.46; 95% CI, 0.25 to 0.79). These data indicate that dysregulated activity of the alternative complement pathway contributes to IgAN pathogenesis in both Asians and Europeans and implicate CFHR3,1Δ as the functional allele at this locus.

Association of Megsin Gene Variants With IgA Nephropathy in Northwest Chinese Population: A STROBE-Compliant Observational Study.

Megsin is a mesangial cell-predominant gene that encodes a serpin family protein which is expressed in the renal mesangium. Overexpression of megsin has been observed in the glomeruli of patients with IgA nephropathy (IgAN). The aim of this study was to evaluate the association of megsin polymorphisms (rs1055901 and rs1055902) with IgAN in a Chinese population.We examined 351 patients with histologically proven IgAN and compared them with 310 age, sex, and ethnicity-matched healthy subjects. Two single nucleotide polymorphisms (SNPs) in megsin were genotyped by Sequenom MassARRAY. SPSS 18.0 was used for statistical analyses, and SNP Stats to test for associations between these polymorphisms and IgAN risk. Odds ratios with 95% confidence intervals were used to assess the relationships.We found that rs1055901 and rs1055902 SNPs were not correlated with susceptibility to IgAN in Northwest Chinese population. Analyses of the relationship between genotypes and clinical variables indicated that in patients with IgAN, rs1055901 was associated with 24-hour proteinuria, an increase in blood pressure, and Lee's grade (P = 0.04, 0.02, and 0.04, respectively), and rs1055902 was associated with 24-hour proteinuria and Lee's grade (P = 0.03 and 0.01, respectively). However, the results showed no association between these gene variants and sex of the patients.These results indicate that megsin gene variants may play a role in the severity, development, and/or progression of IgAN in Northwest Chinese population.

Lack of Association Between Polymorphisms in AGT and ATR1 and IgA Nephropathy in a Chinese Population.

The mechanism of immunoglobulin A nephropathy (IgAN) remains unclear. Genetic factors may be associated with the risk of IgAN. This study aims to identify the possible association of M268T (rs699) in the Angiotensinogen (AGT) gene and A1166C (rs5186) in the Angiotensin II receptor type 1 (ATR1) gene with IgAN risk. Study subjects included 351 patients with IgAN and 310 controls from the Chinese population. The tag SNPs (tSNPs) were genotyped by Sequenom MassARRAY RS1000. Statistical analysis of the association between tSNPs and IgAN was performed using the χ(2) test and SNPStats software. The AGT (M268T) genotypes were distributed in IgAN as CC 61.9%, CT 34.8%, and TT 3.2%, while in controls CC 64.1%, CT 31.3%, and TT 4.6%. Distribution of ATR1 (A1166C) was AA 87.7%, CA 12.3%, and CC 0%, while in controls AA 87.2%, CA 12%, and CC 0.8%. We further analyzed tSNPs under different inheritance models and found that there were no significant differences in the genotypes and allele frequencies of rs699 and rs5186 between two groups (p > 0.05). We also analyzed tSNPs based on the rate of pressure, proteinuria and Lee's classification, and no significant differences were found in the models (p > 0.05). rs699 in the AGT gene and rs5186 in the ATR1 gene were not associated with the risk and clinical outcomes of IgAN.

Association between CCDC132, FDX1 and TNFSF13 gene polymorphisms and the risk of IgA nephropathy.

Previous genome-wide association studies have identified multiple susceptibility loci for IgA nephropathy (IgAN); however, validation of these findings is still needed. We performed a case-control study among 347 Chinese Han IgAN patients and 310 ethnicity-matched controls. Twenty-two single nucleotide polymorphisms (SNPs) were genotyped and association analysis was performed. We found three alleles for IgAN in patients: the allele "C" of rs2188404 in the CCDC132 gene by recessive model (odds ratio (OR), 1.65; 95% confidence interval (CI), 1.10-2.48; P = 0.014) and additive model (OR, 1.29; 95% CI, 1.03-1.61; P = 0.024) analysis, respectively, the allele "A" of rs10488764 in FDX1 gene by additive model (OR, 1.27; 95% CI, 1.00-1.61; P = 0.048) analysis, the allele "A" of rs3803800 in TNFSF13 gene by recessive model (OR, 2.05; 95% CI, 1.16-3.62; P = 0.010) and additive model (OR, 1.35; 95% CI, 1.06-1.72; P = 0.013) analysis, respectively. However, the associations between these SNPs and the risk of IgAN were not significant when adjusted for age and sex. Additionally, we found polymorphisms of rs2188404, rs10488764 and rs3803800 were correlated with urine protein (UPRO), human serum albumin (HSA), total cholesterol (TC) and Lee's pathological grades. We did not find any positive association between these SNPs and the risk of IgAN after adjustment by age and sex, but did find a significant and strong correlation with relevant clinical pathological parameters. Our study may provide a new perspective to understanding the aetiology of IgAN.

Genetic polymorphisms in TNFSF13 and FDX1 are associated with IgA nephropathy in the Han Chinese population

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.

Association between the AGTR1 A1166C polymorphism and risk of IgA nephropathy: a meta-analysis

Numerous studies have evaluated the association between the A1166C polymorphism in the angiotensin II type 1 receptor (AGTR1) gene and immunoglobulin A nephropathy (IgAN) risk. However, this relationship remains controversial. Our aim was to evaluate the relationship between this polymorphism and IgAN susceptibility by performing a meta-analysis. Articles were identified in the PubMed, Google Scholar, and China National Knowledge Infrastructure databases, and after selection, five eligible studies 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 AGTR1 A1166C polymorphism and IgAN risk were not statistically significant [A vs C: OR = 0.64, 95% confidence interval (CI) = 0.24-1.68; AA vs AC+CC: OR = 1.02, 95%CI = 0.74-1.39; CC vs AC+AA: OR = 1.20, 95%CI = 0.48-2.98; AC vs AA+CC: OR = 0.96, 95%CI = 0.70-1.31]. In conclusion, the AGTR1 gene A1166C polymorphism may not be correlated with IgAN susceptibility. However, further studies should be performed to confirm this finding.

RETRACTED: Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy.

The following article has been included in a multiple retraction: Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang and Zhi-Yang Zhou Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy Journal of Renin-Angiotensin-Aldosterone System ( JRAAS) 1470320314563424, first published 18 December 2014. DOI: 10.1177/1470320314563424 . This article has been retracted at the request of the Editors and the Publisher. After conducting a thorough investigation, SAGE found that the submitting authors of a number of papers published in the JRAAS (listed below) had supplied fabricated contact details for their nominated reviewers. The Editors accepted these papers based on the reports supplied by the individuals using these fake reviewer email accounts. After concluding that the peer-review process was therefore seriously compromised, SAGE and the journal Editors have decided to retract all affected articles. Online-first articles (these articles will not be published in an issue) Wenzhuang Tang, Tian-Biao Zhou and Zongpei Jiang Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy JRAAS 1470320314563426, first published 18 December 2014. DOI: 10.1177/1470320314563426 . Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang and Zhi-Yang Zhou Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy JRAAS 1470320314563424, first published 18 December 2014. DOI: 10.1177/1470320314563424 . Weiqiang Zhong, Zongpei Jiang and Tian-Biao Zhou Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population JRAAS1470320314566019, first published 26 January 2015. DOI: 10.1177/1470320314566019 . Tian-Biao Zhou, Xue-Feng Guo, Zongpei Jiang and Hong-Yan Li Relationship between the ACE I/D gene polymorphism and T1DN susceptibility/risk of T1DM developing into T1DN in the Caucasian population JRAAS 1470320314563425, first published 1 February 2015. DOI: 10.1177/1470320314563425 . Chun-Hua Yang and Tian-Biao Zhou Relationship between the angiotensinogen A1166C gene polymorphism and the risk of diabetes mellitus developing into diabetic nephropathy JRAAS 1470320314566221, first published 1 February 2015. DOI: 10.1177/1470320314566221 . Chun-Hua Yang and Tian-Biao Zhou Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression JRAAS 1470320314568521, first published 3 February 2015. DOI: 10.1177/1470320314568521 . Articles published in an issue Guohui Liu, Tian-Biao Zhou, Zongpei Jiang and Dongwen Zheng Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population JRAAS March 2015; 16: 165-171, first published 14 November 2014. DOI: 10.1177/1470320314557849 . Weiqiang Zhong, Zhongliang Huang, Yong Wu, Zongpei Jiang and Tian-Biao Zhou Association of aldosterone synthase ( CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy JRAAS September 2015; 16: 660-665, first published 20 August 2014. DOI: 10.1177/1470320314524011 .

RETRACTED: Association of aldosterone synthase (CYP11B2) gene polymorphism with IgA nephropathy risk and progression of IgA nephropathy

This meta-analysis was conducted to assess the association of aldosterone synthase (CYP11B2) gene polymorphism with the risk of immunoglobulin A (IgA) nephropathy (IgAN) and the progression of IgAN. The literature on associations was identified from PubMed and the Cochrane Library on 1 October 2013, and eligible reports were synthesized. Eligible reports were recruited into this meta-analysis for the association of CYP11B2-344C/T (rs1799998) gene polymorphism with IgAN risk, and the progression of IgAN. In this meta-analysis, the association of CYP11B2-344C/T (rs1799998) gene polymorphism with IgAN risk was not found in overall populations and in Asians. Interestingly, the C allele and CC genotype were associated with the risk of IgAN in Caucasians, but the TT genotype was not. CYP11B2-344C/T gene polymorphism is not associated with IgAN risk and IgAN progression in overall populations and in Asians, but CYP11B2 C allele and CC genotype were associated with the risk of IgAN in Caucasians. However, more studies should be performed in the future to confirm this association.

Association of uteroglobin G38A gene polymorphism with IgA nephropathy risk: an updated meta-analysis

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.

Association of Megsin gene polymorphism with IgA nephropathy risk

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.

Association between plasminogen activator inhibitor-1 4G/5G gene polymorphism and immunoglobulin A nephropathy susceptibility

The association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G gene polymorphism and immunoglobulin A nephropathy (IgAN) risk is still controversial. A meta-analysis was performed to evaluate the association between PAI-1 4G/5G 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 4G/5G gene polymorphism and IgAN risk. 4G allele was not associated with IgAN susceptibility in overall populations and in Asians. Furthermore, 4G/4G and 5G/5G genotype were not associated with IgAN for overall populations, Asians. In conclusion, PAI-1 4G/5G gene polymorphism was not associated with IgAN risk in overall populations and in Asians. However, more studies should be performed in the future.

Association of miR-146a rs2910164 with childhood IgA nephropathy.

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). 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. 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). These results indicated that rs2910164 may affect the susceptibility and severity of pediatric IgAN. Further studies are needed to validate these findings.

Genetic Variants in Interleukin Genes and Susceptibility to IgA Nephropathy: A Meta-Analysis

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.

C509T and T869C polymorphisms of transforming growth factor β1 and the risk of IgA nephropathy: a meta-analysis

Background IgA nephropathy (IgAN) is the most common primary glomerular disease. Transforming growth factor β1 (TGFβ1) plays an important role in pathogenesis of IgAN. Associations between the polymorphisms of TGFβ1 gene and the risk of IgAN remained inconsistent. A meta-analysis was conducted to investigate the association between polymorphisms in the TGFβ1 gene and IgAN susceptibility. Methods Databases including Pubmed, EMBASE, ISI, et al. were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of associations. Results Ten studies involving 1770 cases and 1953 controls were included. Significant association between C509T polymorphism and IgAN risk was observed (OR 1.42, 95% CI 1.12–1.81, P=0.0004; I 2=0%) in Caucasians by the overdominant model (CT vs. CC + TT), but no significant association was found (P=0.200) in Asians by the dominant model (CC + CT vs. TT). Significant association between T869C polymorphism and IgAN susceptibility was found (OR 1.21, 95% CI 1.02–1.44, P=0.030) in overall populations by the dominant model (TT + TC vs. CC). Subgroup analysis found T allele of T869C polymorphism was associated with IgAN susceptibility in Caucasians (P=0.030), but not in Asians (P=0.290). Conclusion Both heterozygotes of C509T polymorphism and T allele of T869C polymorphism in TGFβ1 were associated with the risk of IgAN in Caucasians, but not in Asians.

Increased Risk of IgA Nephropathy Among Individuals With Celiac Disease

To determine the risk of future biopsy-verified IgA nephropathy (IgAN) among individuals with biopsy-verified celiac disease (CD). Individuals with CD suffer increased risk of end-stage renal disease. An association between CD and IgAN has been suggested; however, results have been inconclusive and no previous study has considered the risk of IgAN in biopsy-verified CD. We performed a population-based prospective cohort study. We identified 27,160 individuals with CD (Marsh stage III) and no previous renal disease through small-intestinal biopsy reports obtained between July 1969 and February 2008 in all (n=28) Swedish pathology departments. Individuals with IgAN were identified by biopsy reports acquired at the 4 Swedish pathology departments specialized in renal pathology. Cox regression analysis was used to determine the risk of future IgAN among individuals with CD compared with 133,949 age-matched and sex-matched reference individuals. Seven (0.026%) individuals with CD and 11 (0.008%) reference individuals developed IgAN. We found an increased risk of biopsy-verified IgAN among individuals with CD [hazard ratio, 3.03; 95% confidence interval, 1.22-7.56]. The risk increase remained statistically significant after adjustment for prior liver disease and country of birth. Individuals with CD suffer a 3-fold increased risk of future IgAN. Our findings warrant awareness of renal function in individuals with CD.

A Polymorphism of Interleukin-22 Receptor Alpha-1 Is Associated with the Development of Childhood IgA Nephropathy

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.

Different Recurrence Rates Between Pediatric and Adult Renal Transplantation for IgAN: Predictors of Posttransplantation Recurrence

Purpose: IgA nephropathy (IgAN) is most common primary glomerulonephrits and a major contributor to the renal transplant. Recurrence rates after transplantation(TPL) are high but not well studied. Also, the effect of recipient age and clinical manifestations on recurrence has not been evaluated thoroughly. Purpose of this study is to investigate IgAN recurrence rate after TPL in children and adults and to identify recurrence-associated factors by age. Methods: All consecutive kidneys transplants performed at single center between January 1989 and December 2005 were included in this analysis. Subjects were divided into two group by recipient age (less than or greater than 20 years at the time of transplant). And then, each group was divided into two subgroups based on recurrence. Each groups were analyzed distinctively by the steps of clinical manifestations (fig 1)[Fig 1]Results: A total of 56 patients were enrolled in the study. The recurrence rate was higher in < 20yr with 53.8% than > 20 yr with 23.3% (P = 0.046) (fig 2). However, there was no statistical difference in graft loss between groups. In a subgroup analysis (age), there was no factor noted statistically related to the recurrence in < 20yr. However, progressive symptoms to renal replacement therapy (PS to RRT) was significantly shorter in the recurrent >20yr than in no-recurrent >20yr. The univariate relative risk of recurrent IgAN after transplant for >20yr recipient whose the time of PS to RRT was less than 24 months was 9.8 (95% CI: 1.04-92.70; p = 0.046)[Fig 2]Conclusion: For >20 yr, the recurrent group, in comparison the no-recurrent group, displayed more rapid deterioration from PS to RRT. These results carefully suggest that there are tendencies to recur in adults with rapid deterioration to ESRD. Therefore, renal transplantation may not be needed to hasten in adults with rapid deterioration. Figure 1: Definitions of clinical progression. IS = initial signs; PS = progressive symptoms; RRT = renal replacement therapy Figure 2: Schematic diagram of the study design, groups according to recurrence and age, and outcomes.

Pathogenesis of Immunoglobulin A Nephropathy: Recent Insight from Genetic Studies

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.

Geographic Differences in Genetic Susceptibility to IgA Nephropathy: GWAS Replication Study and Geospatial Risk Analysis

IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10−32–3×10−10), with heterogeneity detected only at the PSMB9/TAP1 locus (I2 = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10−4). A seven–SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10−128). This model paralleled the known East–West gradient in disease risk. Moreover, the prediction of a South–North axis was confirmed by registry data showing that the prevalence of IgAN–attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.