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Association of systemic lupus erythematosus susceptibility genes with IgA nephropathy in a Chinese cohort.

ABSTRACT: BACKGROUND AND OBJECTIVES: One 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, & MEASUREMENTS: This 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. RESULTS: Ninety-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. CONCLUSION: From this "systems genetics" perspective, these data provide important clues for future studies on pleiotropy in IgAN and lupus nephritis.

SUBMITTER: Zhou XJ

PROVIDER: S-EPMC3974348 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Association of systemic lupus erythematosus susceptibility genes with IgA nephropathy in a Chinese cohort.

Zhou Xu-Jie XJ Cheng Fa-Juan FJ Zhu Li L Lv Ji-Cheng JC Qi Yuan-Yuan YY Hou Ping P Zhang Hong H

Clinical journal of the American Society of Nephrology : CJASN 20140123 4

<h4>Background and objectives</h4>One 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.<h4>Design, setting, participants, & measurements</h4>This study investigated whether SNP ...[more]

PMID: 24458077

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Project description:Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P(meta)?=?6.6×10(-8), OR?=?1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta)?=?2.9×10(-7), OR?=?1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1?), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1? (P(meta)?=?3.2×10(-7), OR?=?1.47) conferred a higher risk of SLE than heterozygous deletion (P(meta)?=?3.5×10(-4), OR?=?1.14). These results suggested that the CFHR3-1? deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE.

Dataset Information

Association of systemic lupus erythematosus susceptibility genes with IgA nephropathy in a Chinese cohort.

Publications

Association of systemic lupus erythematosus susceptibility genes with IgA nephropathy in a Chinese cohort.

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