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Identification of new susceptibility loci for IgA nephropathy in Han Chinese.

ABSTRACT: IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10(-10)), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10(-9)) and ODF1-KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 × 10(-9)), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 × 10(-19)), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 × 10(-19); rs12716641, P=9.53 × 10(-9); rs9314614, P=4.25 × 10(-9), multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN.

SUBMITTER: Li M

PROVIDER: S-EPMC4458882 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Identification of new susceptibility loci for IgA nephropathy in Han Chinese.

Li Ming M Foo Jia-Nee JN Wang Jin-Quan JQ Low Hui-Qi HQ Tang Xue-Qing XQ Toh Kai-Yee KY Yin Pei-Ran PR Khor Chiea-Chuen CC Goh Yu-Fen YF Irwan Ishak D ID Xu Ri-Cong RC Andiappan Anand K AK Bei Jin-Xin JX Rotzschke Olaf O Chen Meng-Hua MH Cheng Ching-Yu CY Sun Liang-Dan LD Jiang Geng-Ru GR Wong Tien-Yin TY Lin Hong-Li HL Aung Tin T Liao Yun-Hua YH Saw Seang-Mei SM Ye Kun K Ebstein Richard P RP Chen Qin-Kai QK Shi Wei W Chew Soo-Hong SH Chen Jian J Zhang Fu-Ren FR Li Sheng-Ping SP Xu Gang G Shyong Tai E E Wang Li L Chen Nan N Zhang Xue-Jun XJ Zeng Yi-Xin YX Zhang Hong H Liu Zhi-Hong ZH Yu Xue-Qing XQ Liu Jian-Jun JJ

Nature communications 20150601

IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10(-10)), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10(-9)) and ODF1-KLF10 on 8q22.3 (rs20 ...[more]

PMID: 26028593

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Project description:Several novel susceptibility genes for systemic lupus erythematosus (SLE) and IgA nephropathy have been identified in recent genome-wide association studies. Since both lupus nephritis and IgA nephropathy are autoimmune diseases of the kidney, they may share common disease mechanisms that overlap with genetic susceptibility. To test this hypothesis, we sought to identify genetic variants associated with IgA nephropathy in lupus nephritis.In the first stage, 500 patients with lupus nephritis, 240 SLE patients without nephritis, and 500 healthy controls were enrolled. Fifteen single-nucleotide polymorphisms (SNPs) that had the topmost association signals with IgA nephropathy were selected for further testing in patients with lupus nephritis. Three independent cohorts from Beijing, Shanghai, and Hong Kong were included as replicates. We also analyzed the functional significance of identified noncoding variants on regulatory motifs and gene expression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.In addition to associations with HLA gene polymorphisms, genetic variants of MTMR3 in 22q12 showed associations with lupus nephritis (for rs9983A, OR 1.61 [95% CI 1.19-2.19], P = 2.07 × 10(-3) ) compared to healthy controls in the first stage. Associations were replicated and reinforced among northern Han Chinese (for lupus nephritis patients versus SLE patients without nephritis, P = 0.01) but not southern Han Chinese, although significant genetic heterogeneity was observed. Conservative and regulatory features of rs9983 were predicted in in silico analyses. In expression analysis, we observed lower MTMR3 transcription levels in samples of blood with rs9983A and in renal biopsy samples from lupus nephritis and IgA nephropathy patients.Our results suggest that the MTMR3 gene is shared between IgA nephropathy and lupus nephritis in the northern Chinese population, further highlighting the role of autophagy in SLE. However, widespread replication of these experiments, fine mapping, and functional assays are required to establish this connection.

Project description:The coexistence of immunoglobulin A nephropathy (IgAN) and idiopathic membranous nephropathy (IMN) in a few cases suggested that there could be existed a similar mechanism in pathogenesis of these two types of primary glomerulonephritis. In order to verify this hypothesis, a total of 23 reported IgAN-associated SNPs were genotyped in a cohort of 485 IMN patients and 569 healthy controls with Chinese Han origin. After Cochran-Armitage test for trend analysis, seven IgAN-associated SNPs located in the major histocompatibility complex (MHC) region were found to be significantly associated with the susceptibility of IMN, with rs9275596 as the top one (p = 1.97E-43, OR = 3.977). It was worth mentioning that the minor alleles of the SNPs conferred completely opposite effects on the pathogenesis of IMN and IgAN, suggesting quite different roles played by these SNPs for these two kinds of primary glomerulonephritis. Conditional logistic regression analysis displayed that SNPs protective from IMN (odds ratio < 1.00) were still significantly associated with IMN (p = 3.67E-4 for rs660895 and p = 1.26E-4 for rs9275224) with the most significant SNP rs9275596 as a covariate. Haplotype-based analysis showed that the seven SNPs were mapped to independent linkage disequilibrium (LD) blocks. Moreover, three out of these seven SNPs, including rs9275224, rs660895, and rs9357155, were found to be potential expression quantitative trait loci (eQTLs) for HLA-DQ molecules. Out of the purpose of identifying the causal variants for IMN within the MHC region, imputation analysis was performed using genotype data of Chinese Han released by the 1000 Genome Project and identified hundreds of SNPs potentially associated with the disease. In brief, our analysis revealed a significant association with the susceptibility of idiopathic membranous nephropathy for the IgAN-correlated SNPs. These SNPs conferred a completely different role for the pathogenesis of these two kinds of diseases.

Project description:Background and objectivesOne hypothesis states that IgA nephropathy (IgAN) is a syndrome with an autoimmune component. Recent studies strongly support the notion of shared genetics between immune-related diseases. This study investigated single-nucleotide polymorphisms (SNPs) reported to be associated with systemic lupus erythematosus (SLE) in a Chinese cohort of patients with IgAN and in controls.Design, setting, participants, & measurementsThis study investigated whether SNP markers that had been reported to be associated with SLE were also associated with IgAN in a Chinese population. The study cohort consisted of 1194 patients with IgAN and 902 controls enrolled in Peking University First Hospital from 1997 to 2008.ResultsNinety-six SNPs mapping to 60 SLE loci with reported P values <1 × 10(-5) were investigated. CFH (P=8.41 × 10(-6)), HLA-DRA (P=4.91 × 10(-6)), HLA-DRB1 (P=9.46 × 10(-9)), PXK (P=3.62 × 10(-4)), BLK (P=9.32 × 10(-3)), and UBE2L3 (P=4.07 × 10(-3)) were identified as shared genes between IgAN and SLE. All associations reported herein were corroborated by associations at neighboring SNPs. Many of the alleles that are risk alleles for SLE are protective alleles for IgAN. By analyses of two open independent expression quantitative trait loci (eQTL) databases, correlations between genotypes and corresponding gene expression were observed (P<0.05 in multiple populations), suggesting a cis-eQTL effect. From gene-expression databases, differential expressions of these genes were observed in IgAN. Additive interactions between PXK rs6445961 and HLA-DRA rs9501626 (P=1.51 × 10(-2)), as well as multiplicative interactions between CFH rs6677604 and HLA-DRB1 rs9271366 (P=1.77 × 10(-2)), and between HLA-DRA rs9501626 and HLA-DRB1 rs9271366 (P=3.23 × 10(-2)) were observed. Disease risk decreased with accumulation of protective alleles. Network analyses highlighted four pathways: MHC class II antigen presentation, complement regulation, signaling by the B-cell receptor, and ubiquitin/proteasome-dependent degradation.ConclusionFrom this "systems genetics" perspective, these data provide important clues for future studies on pleiotropy in IgAN and lupus nephritis.

Dataset Information

Identification of new susceptibility loci for IgA nephropathy in Han Chinese.

Publications

Identification of new susceptibility loci for IgA nephropathy in Han Chinese.

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