IgA Nephropathy Susceptibility Research Articles

Association of genetic polymorphisms in IL-23R and IL-17A with the susceptibility to IgA nephropathy in a Chinese Han population.

IgA Nephropathy (IgAN) is one of the most common causes of chronic kidney damage worldwide. Identifying new genetic factors associated with IgAN risk is of invaluable importance. To explore the association between polymorphisms of IL-23R and IL-17A and the susceptibility of IgAN, 164 IgAN patients and 192 healthy controls were genotyped for five SNPs in a Chinese Han population. A comparative analysis between genotype distributions, clinical indexes and pathological grades in the IgAN patients was also performed. The GG genotype and a G allele of rs7517847 were associated with a decreased IgAN risk (OR: 0.545; 95% CI: 0.299-0.993; p = 0.046; OR: 0.730; 95% CI: 0.541-0.984; p = 0.039) compared to the TT genotype and T allele respectively. Furthermore, the AA genotype of rs2275913 appeared to reduce the IgAN risk (OR: 0.405; 95% CI: 0.209-0.786; p = 0.007) compared to the GG genotype. Consistently, individuals harboring an AA genotype had a lower IgAN risk (OR: 0.380; 95% CI: 0.211-0.686; p = 0.001) under the recessive model. Our study demonstrated for the first time the significant associations of rs7517847 in IL-23R and rs2275913 in IL-17A with the risk of IgAN in Chinese Han.

The Influence of ACE Insertion/Deletion Gene Polymorphism on the Risk of IgA Nephropathy: A Debatable Topic.

Background The connection between angiotensin-converting enzyme insertion/deletion (ACE I/D) gene polymorphisms and IgA nephropathy (IgAN) was conflicting. This pooled analysis was performed to explore this issue. Methods All eligible investigations were identified from various electronic databases, and the pooled analysis was evaluated using Stata software. Results 27 studies with 2538 IgAN cases and 3592 controls were included. In overall subjects, ACE D allele, DD, and II genotype were associated with IgAN susceptibility (D vs. I: OR = 1.21, 95% CI: 1.10–1.32, P < 0.001; DD vs. ID + II: OR = 1.38, 95% CI: 1.20–1.60, P < 0.001; and II vs. DD + ID: OR = 0.83, 95% CI: 0.73–0.95, P=0.007). In Asian and Chinese patients, ACE I/D gene polymorphism was also correlated with IgAN vulnerability. Moreover, ACE D allele, DD, and II genotype were correlated with the progression of IgAN (D vs. I: OR = 1.37, 95% CI: 1.09–1.73, P=0.008; DD vs. ID + II: OR = 1.57, 95% CI: 1.06–2.31, P=0.024; and II vs. DD + ID: OR = 0.69, 95% CI: 0.49–0.99, P=0.045). Conversely, in Caucasian subjects, there was no link between ACE I/D gene polymorphism and the risk of IgAN. Conclusion ACE I/D gene polymorphism was correlated with the vulnerability and progression of IgAN in Asian and Chinese patients, and ACE D allele and DD homozygote genotype could be adverse factors for IgAN, while the II homozygote genotype could be an advantage factor. But, no significant association was found between ACE I/D gene polymorphism and IgAN in Caucasians.

MIR17HG genetic variations affect the susceptibility of IgA nephropathy in Chinese Han people.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide. It accounts for approximately 30~40% of glomerular diseases in China. However, the exact pathogenesis of IgAN is not well established. This study aimed to explore the association between MIR17HG polymorphisms and IgAN susceptibility. Six single nucleotide polymorphisms (SNPs) of MIR17HG were genotyped in 417 patients with IgAN and 424 healthy controls. The association analysis was conducted by logistic regression adjusted for age and gender in multiple genetic models and different subgroups. Our results revealed that rs72640334 and rs1428 increased the susceptibility to IgAN in total populations (p<0.05). The stratification analysis by age indicated that rs72640334 enhanced the risk of IgAN people older than 35years, while rs7318578 played a protective role in the development of IgAN patients aged >35years (p<0.05). In addition, MIR17HG-rs72640334 could facilitate the occurrence of IgAN in females (p<0.05). In Lee's grade III-Vsubgroup, rs72640334 and rs7336610 have an increasing effect on IgAN risk, while rs7318578 has a decreasing effect on IgAN susceptibility (p<0.05). Our findings suggested that MIR17HG genetic polymorphisms were correlated with IgAN susceptibility. It provided new evidence for the potential molecular mechanism of IgAN and may serve as a new biomarker for the treatment and early diagnosis of IgAN.

A Functional Variant rs3093023 in CCR6 Is Associated With IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population.

C-C chemokine receptor 6 (CCR6) is a susceptibility gene of various immune-related diseases, which was suggested to be shared with immunoglobulin A nephropathy (IgAN). In this study, we aimed to identify the functional variants. First, we analyzed the associations of CCR6 common and rare variants detected by multi-platform chips with IgAN susceptibility using imputation and identified 68 significantly associated common variants located in the regulatory region. Among them, rs3093023 showed both statistical significance (rs3093023-A, odds ratio [OR] = 1.15, P = 2.00 × 10−2) and the expression quantitative trait loci (eQTL) effect (P = 1.45 × 10−3). It was independently replicated (rs3093023-A, OR = 1.18, P = 5.56 × 10−3) and the association was reinforced in the meta-analysis (rs3093023-A, OR = 1.17, P = 6.14 × 10−7). Although rs3093023 was in a strong linkage disequilibrium with the reported CCR6 functional variant dinucleotide polymorphism, CCR6DNP, the alleles of rs3093023 (G>A) rather than of CCR6DNP were shown differential nuclear protein binding effect by electrophoretic mobility shift assay. The RegulomeDB and JASPAR databases predicted Pou2f1 as the potential transcription factor, which was negatively associated with CCR6 mRNA (r = −0.60, P = 3.94 × 10−9). At the mRNA level, the eQTL effect of CCR6 was validated (P = 4.39 × 10−2), and CCR6 was positively associated with the expression of CCR4 and IL-17A rather than that of CXCR3 and IFNG. At the protein level, a higher CCR6+ cell ratio was observed in a risk allele dose-dependent manner in lymphocytes (P = 3.57 × 10−2), CD3+ T cells (P = 4.54 × 10−2), and CD4+ T cells (P = 1.32 × 10−2), but not in CD8+ T cells. Clinical-pathological analysis showed that rs3093023 risk allele was significantly associated with diastolic blood pressure, serum creatinine, and high ratio of tubular atrophy/interstitial fibrosis. Overall, the rs3093023 was prioritized as the function variant in CCR6, which may contribute to IgAN susceptibility by regulating Th17 cells.

ST6GAL1 polymorphisms influence susceptibility and progression of IgA nephropathy in a Chinese Han population.

ST6GAL1 has been identified as a novel susceptibility gene for IgA nephropathy (IgAN) in a previous genome-wide association study. The present study is aimed at exploring whether the genetic polymorphisms of ST6GAL1 gene correlate with IgAN susceptibility, clinical phenotypes and progression in a Chinese Han population. Twenty-six single nucleotide polymorphisms (SNPs) of ST6GAL1 were genotyped in 1000 biopsy-proven IgAN patients and 1000 control subjects of Chinese Han population using Sequenom MassARRAY iPLEX. A logistic regression analysis with age and sex as covariates was performed to evaluate the effects of ST6GAL1 gene polymorphisms on IgAN susceptibility. Kaplan-Meier method and Cox proportional hazard models were applied to analyze the associations between genetic variants and renal survival. We found that rs7634389 (OR = 1.24, 95 % CI = 1.02-1.50, pdominant = 0.034) and rs6784233 (OR = 1.23, 95 % CI = 1.05-1.45, padditive = 0.013; OR = 1.28, 95 % CI = 1.05-1.55, pdominant = 0.014) were associated with susceptibility of IgAN. In addition, rs7634389 was correlated with hyperuricemia (OR = 1.27, p = 0.012) and segmental glomerulosclerosis (OR = 1.21, p = 0.047) in IgAN patients. Furthermore, rs7634389 was independently associated with renal survival after adjustments for multiple confounders (hazard ratio [HR] = 0.51, 95 % CI = 0.33-0.78, p = 0.002). Haplotype analysis for ST6GAL1 polymorphisms confirmed their associations with the susceptibility to IgAN. Our research suggested that ST6GAL1 gene polymorphisms were implicated in IgAN susceptibility and clinical outcome in a Chinese Han population.

Genetic variants of the MIR31HG gene are related to a risk of IgA nephropathy

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Previous studies reveal that genetic factors play a crucial role in IgAN progression. This study was conducted to investigate the association between MIR31HG variants and IgAN risk.A total of 836 subjects were recruited to detect the relationship of MIR31HG variants with IgAN susceptibility. Odds ratios (OR) and 95% confidence intervals (CI) were computed to evaluate the associations. Multifactor dimensionality reduction was performed to analyze the SNP-SNP interaction with IgAN risk.Our study showed that rs1332184 and rs55683539 significantly related to an increased risk of IgAN (OR 1.34, p = 0.041; OR 1.39, p = 0.025). Stratified analyses indicated rs72703442, rs55683539, and rs10965064 exhibited strongly enhanced risk of IgAN in age ≤ 35 years (OR 1.55, p = 0.023; OR 1.60, p = 0.012; OR 1.46, p = 0.037). Besides, we found rs1332184, rs55683539 and rs2181559 significantly increased the susceptibility of IgAN in males (OR 1.71, p = 0.003; OR 1.44, p = 0.042; OR 1.60, p = 0.010). We also observed that rs1332184 could enhance IgAN risk for Lee’s grade ≥ III (OR 1.39, p = 0.045). Rs55683539 significantly increased a risk of IgAN (OR 1.58, p = 0.027), while rs2025327 had a lower risk of IgAN in Lee’s grade < III (OR 0.46, p = 0.007). Interestingly, we found rs72703442 polymorphism was related to hemoglobin (p = 0.043), and rs10965064 was associated with Urine red blood cell (p = 0.040).Our study proposed that MIR31HG polymorphisms associate with susceptibility to IgAN in Chinese population.

Three SNPs of FCRL3 and one SNP of MTMR3 are associated with immunoglobulin A nephropathy risk.

Immunoglobulin A nephropathy (IgAN) is determined by a combination of multiple genetic and environmental factors, but its etiology and pathogenesis are not well understood. We aim to determine whether variations in FCRL3 and MTMR3 correlate with IgAN risk indices in Chinese Han people. Eight single nucleotide polymorphisms (SNPs) of FCRL3 and MTMR3 were genotyped, and association analysis was performed. A total of 426 patients with IgAN and 498 healthy individuals, serving as the control group, were recruited for this association study. There were significant associations between FCRL3 rs11264793 (OR = 0.78; 95 % CI = 0.63-0.98; p = 0.029), rs11264794 (OR = 0.81; 95 % CI = 0.67-0.98; p = 0.026) and rs7522061 (OR = 0.79; 95 % CI = 0.65-0.95; p = 0.012) and decreased risk of IgAN according to allele model results. Under genetic models, FCRL3 and MTMR3 were associated with the risk of IgAN. Interestingly, FCRL3 reduced the IgAN susceptibility only in females, while MTMR3 was a risk factor for IgAN only in males. In addition, FCRL3 rs11264793 and rs7522061 were significantly associated with a decreased risk of IgAN in different disease grades. Moreover, the haplotypes ACC (p = 0.02) and CTC (p = 0.017) of LD block rs11264794/rs7522061/rs11264799 in the FCRL3 gene were significantly associated with a decreased risk of IgAN. We suggest that three SNPs of FCRL3 were associated with a decreased risk of IgAN, while one SNP of MTMR3 was associated with an increased risk of IgAN in Chinese Han populations. These findings may be useful in the development of early prognostics for IgAN.

Association of FCRL3 Gene Polymorphisms with IgA Nephropathy in a Chinese Han Population.

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.

Complement factor H gene polymorphism rs6677604 and the risk, severity and progression of IgA nephropathy: A systematic review and meta-analysis.

Studies reporting the association between complement factor H gene rs6677604 polymorphism and susceptibility to IgA nephropathy (IgAN) had yielded inconsistent results. We performed a systematic review and meta-analysis to clarify the association between rs6677604 and IgAN susceptibility, disease severity and chronic progression. A comprehensive database search was performed to identify eligible studies. Meta-analyses were performed for rs6677604 allele frequency, genotypes and the association with IgAN susceptibility. 10 studies were included in the systematic review. Among them, four studies containing 10 distinct datasets (15,617 cases and 31,957 controls) were included in the meta-analysis. The pooled frequency of the minor allele (A) was significantly higher in Europeans than in Asians across both IgAN cases and controls, and the frequency of the minor allele (A) in IgAN cases was also significantly lower than that in controls across both European and Asian subgroups. Significant associations were detected between rs6677604 and risk of developing IgAN, when comparing allele A vs. G, genotype AA vs. GG, genotype AA vs. AG and genotype AG vs. GG. In analysis stratified by ethnicity, significant association was only observed in Europeans but not in Asians when comparing AA vs. GG or AA vs. AG. Our pooled analysis showed a significant association between rs6677604-(A) allele and IgAN susceptibility, supporting the importance of complement activation in the pathogenesis of IgAN. The presence of rs6677604-(A) allele may be associated with a decreased the risk of IgAN in Europeans, but the association was not confirmed in Asians.

Circulating complement factor H–related protein 5 levels contribute to development and progression of IgA nephropathy

IgA nephropathy (IgAN) is a disease associated with activation of the complement system. But the factors influencing complement activation in IgAN are not fully understood. Complement factor H (FH) is an essential negative regulator of complement C3 activation. Complement factor H-related protein (FHR)-5 shares high sequence similarity with factor H. However, unlike factor H, on binding to activated C3 it enables further activation to proceed. Previously, we reported the contribution of rare variants of the CFHR5 gene to IgAN susceptibility. Here we compared circulating levels of FHR-5 in 1126 patients with IgAN and regular follow-up with those of 153 unrelated healthy individuals to explore the relationship of FHR-5 levels with IgAN development and progression. Circulating FHR-5 levels were significantly elevated in patients with IgAN compared to healthy individuals (median 4.55 [interquartile range 3.58 to 5.85] μg/ml vs 3.19 [interquartile range 2.55 to 3.92] μg/ml). Higher circulating FHR-5 levels were associated with a lower estimated glomerular filtration rate, hypertension, and severe Oxford-T and Oxford-C scores. High FHR-5 levels were independently and significantly associated with a risk of developing either a 30% decline in the estimated glomerular filtration rate or end-stage renal disease (hazard ratio, per standard deviation increment of natural square root transformed FHR-5 of 1.226; 95% confidence interval: 1.106-1.359). Thus, the circulating FHR-5 level is an independent risk factor for IgAN progression.

Coding and Noncoding Variants in CFH Act Synergistically for Complement Activation in Immunoglobulin A Nephropathy

BackgroundIn immunoglobulin A nephropathy (IgAN), complement activation occurs in both the systemic circulation and in situ (glomerular). A recent IgAN-genome-wide association study (GWAS) identified 1q32 as an IgAN susceptible locus that contained the complement regulatory protein coding gene complement factor H (CFH). Here, we explored the combined genetic effects of coding and noncoding variants in CFH, rs6677604 and rs800292 on complement activation in IgAN. MethodsIn total, 1,194 IgAN patients and 900 healthy controls who were the same as the Beijing Discovery Cohort in our recent IgAN-GWAS were recruited. The genotyping information of rs800292 and rs6677604 were extracted from GWAS data, while the information regarding plasma C3 levels and mesangial C3 deposits were collected from medical records. ResultsWe found both rs800292-GG and rs6677604-GG were risk genotypes for complement activation in IgAN patients, as represented by lower plasma C3 levels in IgAN patients with rs800292-GG and a higher intensity of glomerular C3 deposits in those with rs6677604-GG, respectively. Additionally, IgAN patients with 2 risk genotypes (rs800292-GG and rs6677604-GG) showed a higher degree of complement activation compared to those with no risk genotypes (rs800292-AA/AG and rs6677604-AA/AG), as represented by both lower plasma C3 levels and a higher intensity of glomerular C3 deposits. Moreover, when compared to rs800292 or rs6677604 alone, the combined genetic effects of rs800292 and rs6677604 showed a stronger association with IgAN susceptibility. ConclusionsOur findings suggested that both coding and noncoding variants in CFH acted synergistically to regulate the degree of complement activation and thereby contributed to IgAN susceptibility.

Genetic polymorphisms in HLA-DP and STAT4 are associated with IgA nephropathy in a Southwest Chinese population.

IgA nephropathy (IgAN) is the most common chronic glomerular disease worldwide. Genetic factors are thought to be crucial in the pathogenesis of IgAN. However, few data are available on the relationship between human leucocyte antigen (HLA) and signal transducer and activator of transcription 4 (STAT4) polymorphisms and IgAN susceptibility in the Chinese population. Therefore, we examined HLA-DP/DQ and STAT4 polymorphisms (rs3077, rs9277535, rs7453920 and rs7574865) in a total of 630 subjects including 140 IgAN and 490 healthy controls in Chinese. There were significant associations between IgAN patients and healthy controls in the allele frequency of rs3077, rs9277535 and rs7574865. In addition, the genotypes of rs3077, rs9277535 and rs7574865 were also significantly associated with IgAN under recessive models. Moreover, the haplotypes block AAG, AGG, GAG and GGA in the HLA gene significantly correlated with the risk of IgAN. This is the first study demonstrating the significant associations of SNP rs3077, rs9277535 and rs7574865 and the haplotypes in the HLA gene with the risk of IgAN in a Southwest Chinese population. This research provides a new insight into the significant relationship between HLA-DP and STAT4 polymorphisms and the susceptibility to IgAN.

Replication of genome‐wide association study identified seven susceptibility genes, affirming the effect of rs2856717 on renal function and poor outcome of IgA nephropathy

Meta-analysis of data from a genome-wide association study (GWAS) identified seven single nucleotide polymorphisms (SNPs) as strong predictors of IgA nephropathy (IgAN). To replicate the association of these seven SNPs and understand whether they influence the clinical characteristics of IgAN, a case-control study including 521 IgAN patients and 535 controls was conducted in a Western Han cohort. Data were analyzed using logistic regression and multifactor dimensionality reduction (MDR). Clinical data collected from 459 IgAN patients were investigated to estimate the relationship between the genotype and phenotype of IgAN. A retrospective cohort study of 315 IgAN patients was conducted to investigate the relationship between genotype and progression of renal disease over a mean period of 44.49 ± 19.94 months. Upon Bonferroni correction, none of the seven SNPs were associated with IgAN (corrected P-value [Pc], >0.05). A combination of the rs2856717T/C, rs9275596C/T, and rs2412971A/G had effects on the susceptibility of IgAN (P = 0.001). Marginally significant association of rs2856717 T/C recessive model for the T allele was significantly associated with estimated glomerular filtration rate (eGFR) (<60 mL/min per 1.73 m2 ) in IgAN patients (P = 0.008, Pc = 0.056, odds ratio [OR] = 1.527). The T allele at rs9275596 was significantly associated with macroscopic haematuria of IgAN patients under the dominant and additive models of inheritance, (P < 0.001, Pc = 0.007, OR = 2.983) and (P < 0.001, Pc = 0.007, OR = 2.17), respectively. Kaplan-Meier survival analysis showed that patients carrying the TT + TC genotype for rs2856717 had reduced renal survival rate than those carrying the CC genotype (85.1% vs. 92.7%, P = 0.046). rs2856717 may influence the clinical characteristics and poor outcome of IgAN. Further studies are warranted to explore the mechanisms for such genotype-disease phenotype association.

Association between MPHOSPH6 gene polymorphisms and IgA nephropathy risk in a Chinese Han population

Multiple genetic and environmental factors together contribute to the risk of IgA nephropathy (IgAN). MPHOSPH6 play an important role in the recruitment of the exosome to the pre-rRNA. However, to date, little information is found about the association between MPHOSPH6 polymorphisms and the IgAN risk. In this case-control study, we genotyped five single nucleotide polymorphisms (SNPs) in MPHOSPH6 gene in 416 IgAN cases and 495 controls using Sequenom Mass-ARRAY technology and evaluated their association with IgAN using the χ2 and genetic model analysis. In the allelic model analysis, we determined rs1056654 was associated with a 0.774-fold decrease in the risk of IgAN (95%CI= 0.630-0.952; p = 0.015). In the genetic model analysis, we found that the “C/C” genotype of rs1056675 was associated with an increased risk of IgAN based on the codominant model (OR =1.48; 95% CI=1.03-2.13; p=0.033) and recessive model (OR =1.52; 95% CI=1.11-2.09; p=0.0095). The “G/A-A/A” genotype of rs1056654 was associated with a decreased risk of IgAN based on the dominant model (OR =0.75; 95% CI=0.58-0.98; p=0.032) and log-additvie model (OR =0.78; 95% CI=0.64-0.96; p=0.0188). Our data suggested that gene polymorphisms in the MPHOSPH6 may exert influences IgAN susceptibility in a Chinese Han population.

Association of TNFSF13 polymorphisms with IgA nephropathy in a Chinese Han population.

Our previous genome-wide association study of IgA nephropathy (IgAN) in a Chinese Han population suggested that the TNFSF13 gene may be a novel susceptibility gene for IgAN. In the present study, we aimed to further evaluate the associations of single-nucleotide polymorphisms (SNPs) and expression level of the TNFSF13 gene with the risk and clinical parameters of IgAN. Six candidate SNPs were selected for genotyping by Sequenom MassARRAY iPLEX in 1000 IgAN cases and 1000 controls. Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) with adjustment for age and sex. Serum APRIL (encoded by the TNFSF13 gene) level was detected by an enzyme-linked immunosorbent assay. We found that rs3803800 was significantly associated with the susceptibility of IgAN after Bonferroni correction [padditive =0.0009, OR (95% CI)=1.25 (1.09-1.42); precessive =0.0006, OR (95% CI)=1.54 (1.20-1.96)]; however, the association remained only in women after further sex-stratified analysis. Genotype-phenotype correlation analysis showed significant associations of rs3803800 with severe clinicopathological manifestations in IgAN patients after adjusting for age and sex, as well as the other two SNPs (rs4246413 and rs4968210) that were also associated with specific clinical phenotypes. Compared with healthy controls, serum APRIL levels were significantly higher in IgAN patients (p=0.0001) and associated with severity of disease. The results of the present study indicate that the genetic variations and gene expression level of TNFSF13 are associated with the susceptibility and severity of IgAN in a Han Chinese population.

Determination of IL-1B (rs16944) and IL-6 (rs1800796) genetic polymorphisms in IgA nephropathy in a northwest Chinese Han population.

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, but etiology and pathogenesis continue to be poorly understood. Polymorphisms in the cytokine genes may play a role in the etiology and pathogenesis of IgAN. The incidence of different between diverse ethnic groups suggested important genetic influences on its pathogenesis.We genotype 10 single nucleotide polymorphisms (SNPs) in IL-1B and IL-6 gene using Sequenom Mass-ARRAY technology from 417 IgAN patients and 463 healthy controls of the Chinese Han population. We evaluated these SNPs associated with IgAN utilising the chi-square tests and genetic model analysis.We identified that the minor alleles of rs16944 (“A”), rs1800796 (“G”) in IL-1B, IL-6 were involved in an increasingly risk of IgAN in allelic model analysis, respectively. The rs16944 in IL-1B and rs1800796 in IL-6 were associated with 1.23-fold (95% CI, 1.02-1.48, P = 0.031) and 1.33-fold (95% CI, 1.11-1.66, P = 0.003) increases in the risk of developing IgAN, respectively. There was only rs1800796 still correlated with IgAN in the allelic model after adjustment by age and gender and the Bonferroni correction. In addition, Haplotype Grs1800796A rs2069837G rs2069840 (P = 0.037) and G rs1800796A rs2069837C rs2069840 (P = 0.042) in IL-6were considered to be associated with increased IgAN risk.This study verified the IL-6, IL-1B genetic variants polymorphisms contributed to IgAN susceptibility in a Chinese Han population. Although we identified SNPs susceptibility, however, replication studies and functional research are required to confirm the genetic contribution in IgAN.

MP191VARIANTS OF IL1B, IL6 GENE ARE ASSOCIATED WITH THE GENETIC SUSCEPTIBILITY TO IGA NEPHROPATHY IN HAN CHINESE PEOPLE

MP191VARIANTS OF IL1B, IL6 GENE ARE ASSOCIATED WITH THE GENETIC SUSCEPTIBILITY TO IGA NEPHROPATHY IN HAN CHINESE PEOPLE

Association Between IFN-γ Gene Polymorphisms and IgA Nephropathy in a Chinese Han Population

Background/Aims: IFN-γ was reported to be involved in the development and progression of Immunoglobulin A nephropathy (IgAN), however, few studies have investigated the association between IFN-γ polymorphisms and IgAN. Therefore, we performed a case-control study to assess the association between IFN-γ polymorphisms and the risk of IgAN. Methods: Sequenom MassARRAY was used to genotype two SNPs (rs1861494 and rs2430561) in 351 patients with IgAN and 310 healthy controls. Associations were evaluated as odd ratios (OR) with 95% confidence intervals (CI). Results: No association was found between IFN-γ rs1861494 and IgAN risk or clinical parameters. For rs2430561, the AA genotype was more common in patients with IgAN, compared with controls (AT vs. AA: OR = 0.57, P = 0.035). IFN-γ-rs2430561 T allele may be a protective factor for IgAN susceptibility (T vs. A: OR = 0.59, P = 0.04). Subgroup analysis based on clinical features revealed no significant association between rs2430561 polymorphism and clinical data such as gender, 24-h urine protein, blood pressure, Oxford classifcation and estimated glomerular fltration rate. IgAN patients had a higher IFN-γ serum level than healthy controls and patients with rs1861494 AA genotype had a higher IFN-γ serum level compared with those with AG/GG genotypes. Conclusions: IFN-γ polymorphisms may be involved in the development and progression of IgAN.

DQB1*060101 may contribute to susceptibility to immunoglobulin A nephropathy in southern Han Chinese.

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.

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.