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Article Association of Systemic Lupus Erythematosus Article Association of Systemic Lupus Erythematosus Susceptibility Genes with IgA Nephropathy in a Chinese Cohort Xu-Jie Zhou, Fa-Juan Cheng, Li Zhu, Ji-Cheng Lv, Yuan-Yuan Qi, Ping Hou, and Hong Zhang Abstract Background and objectives One hypothesis states that IgA nephropathy (IgAN) is a syndrome with an Renal Division, Peking University First autoimmune component. Recent studies strongly support the notion of shared genetics between immune-related Hospital; Peking diseases. This study investigated single-nucleotide polymorphisms (SNPs) reported to be associated with University Institute of systemic lupus erythematosus (SLE) in a Chinese cohort of patients with IgAN and in controls. Nephrology; Key Laboratory of Renal Disease, Ministry of Design, setting, participants, & measurements This study investigated whether SNP markers that had been Health of China; and reported to be associated with SLE were also associated with IgAN in a Chinese population. The study cohort Key Laboratory of consisted of 1194 patients with IgAN and 902 controls enrolled in Peking University First Hospital from 1997 to Chronic Kidney 2008. Disease Prevention and Treatment (Peking University), Ministry , 3 25 Results Ninety-six SNPs mapping to 60 SLE loci with reported P values 1 10 were investigated. CFH of Education, Beijing, 2 2 2 2 2 (P=8.41310 6), HLA-DRA (P=4.91310 6), HLA-DRB1 (P=9.46310 9), PXK (P=3.62310 4), BLK (P=9.32310 3), People’s Republic of and UBE2L3 (P=4.0731023) were identified as shared genes between IgAN and SLE. All associations reported China 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) Correspondence: databases, correlations between genotypes and corresponding gene expression were observed (P,0.05 in mul- Dr. Hong Zhang, Renal Division, Peking tiple populations), suggesting a cis-eQTL effect. From gene-expression databases, differential expressions of these University First genes were observed in IgAN. Additive interactions between PXK rs6445961and HLA-DRA rs9501626 Hospital, Peking (P=1.5131022), as well as multiplicative interactions between CFH rs6677604 and HLA-DRB1 rs9271366 University Institute of (P=1.7731022), and between HLA-DRA rs9501626 and HLA-DRB1 rs9271366 (P=3.2331022) were observed. Nephrology, No. 8 Xi Shi Ku Street, Xi Disease risk decreased with accumulation of protective alleles. Network analyses highlighted four pathways: Cheng District, Beijing MHC class II antigen presentation, complement regulation, signaling by the B-cell receptor, and ubiquitin/ 100034, People’s proteasome-dependent degradation. Republic of China. Email: hongzh@bjmu. Conclusion From this “systems genetics” perspective, these data provide important clues for future studies on edu.cn pleiotropy in IgAN and lupus nephritis. Clin J Am Soc Nephrol 9: 788–797, 2014. doi: 10.2215/CJN.01860213 Introduction identified loci collectively explain ,10% of the genetic Over the past two decades, considerable progress has risk for IgAN, highlighting the fact that much of the been made in unraveling the complex pathogenesis of heritable basis for IgAN has yet to be identified. IgA nephropathy (IgAN). However, the exact patho- Previously, we reported that genetic factors have an genesis remains poorly determined. Current data sug- appreciable influence on the production of under- gest that genetic factors combined with environmental galactosylated IgA1 and that GWAS data strongly factors lead to increased synthesis of aberrantly implicate new clues as to the pathogenesis of IgAN galactosylated IgA1, formation of glycan-specificanti- (7,8,11–15). We also reported on the overlap between bodies to IgG and IgA, and mesangio-podocytic-tubular several autoimmune diseases: systemic lupus erythema- cross-talk in the occurrence and development of the tosus (SLE), rheumatoid arthritis, ANCA-associated disease (1–6). Whether IgAN should be termed an “au- small vasculitis, and anti–glomerular basement toimmune disease” is controversial. However, recent membrane disease (16–25). Thus, we hypothesized genome-wide association studies (GWAS) strongly in- that refinement of GWAS data or identification of dicate that many of its associated loci also affect other IgAN susceptibility genes could be underpinned by autoimmune and infectious diseases (5,7–9), further investigation of the genetic variants reported to be supporting the notion of shared genetics of immune- associated with other immune-related diseases. Iden- related diseases (10). Recent estimates suggest that the tification of novel IgAN genes and shared genetic 788 Copyright © 2014 by the American Society of Nephrology www.cjasn.org Vol 9 April, 2014 Clin J Am Soc Nephrol 9: 788–797, April, 2014 Shared Genetic Study in IgAN and SLE, Zhou et al. 789 pathways could improve understanding of common ge- Statistical Analyses netic mechanisms and eventually the development of im- Only SNPs meeting the quality-control criteria of ,1% proved methods of diagnosis, prognosis, and targeted overall missing data as well as consistency with Hardy– therapies. Weinberg equilibrium genotype frequency expectations SLE is an autoimmune disease. Lupus nephritis is charac- (P,0.05) were included. As reported previously, after ad- terized by multiple immune complexes depositing in the justment for population substructure, the inflation factor kidney, including IgA molecules. IgAN is an immune using all SNPs was l=1.02, indicating a minimal effect of complex–mediated GN defined by the predominant IgA residual population structure. Thus, no further genomic molecule that deposits in the kidney. A recent study showed control corrections were applied. the pathogenicity of anti-glycan antibodies in IgAN, which Genotype frequencies between IgAN cases and controls suggested that IgAN is a type of autoimmune disease (26). A were compared using the chi-squared trend test implemented new theory suggests that most types of GN are primarily in PLINK software to determine whether individual SLE autoimmune diseases. Certain pathogenic similarities be- susceptibility loci were also associated with IgAN. Genetic tweenautoimmunediseases(e.g., greater prevalence among models were defined relative to the minor allele. To reduce the Asians than Europeans, chronic course, renal involvement, risk of false-positive findings, all positive associations were circulating immune complexes, complement activation, mor- checked further by associations at neighboring SNPs. phologic similarities, certain pathways being involved in To test for additive interactions, the methods were taken ESRD) prompted us to investigate the overlap in genetic using a 232 factorial design to calculate the attributable susceptibility between SLE and IgAN. Well established co- proportion due to interaction, the relative excess risk due occurrences of SLE with IgAN suggest common etiologic to interaction, and the synergy index (20,43). P values factors (27–29). Little progress has been made regarding ,0.05 for attributable portion due to interaction were con- the identification of genetic factors specific to lupus nephri- sidered to be indicators of additive interactions. Ninety- tis, but a genetic cause in SLE has been substantiated. More five percent confidence intervals (95% CIs) were calculated than 40 genes have been robustly associated with SLE. using the delta method (44). Multiplicative interaction was We investigated whether single-nucleotide polymorphism assessed by adding an interaction variable (SNP3SNP) to (SNP) markers that had been reported to be associated with the regression models. P,0.05 was considered to be evi- SLE were also associated with IgAN in a Chinese population. dence for multiplicative interactions. Analyses of carriage of SLE alleles in patients with IgAN were carried out to determine whether there was an overall Materials and Methods enrichment of SLE susceptibility variants in IgAN cases. The protocol of this study complied with the Declaration Analyses were also undertaken to determine whether com- of Helsinki. The protocol was approved by the Ethics Com- bining those risk alleles conferred a higher risk of disease. mittee of Peking University First Hospital (Beijing, China). Written informed consent was obtained from each patient. Analyses of Bioinformatics To explore whether the identified SNPs had expression Study Population quantitative trait loci (eQTLs) effects, Genevar software The samples used in the present study have been described was used to determine associations between sequence previously. Briefly, exclusion of duplicates and first-degree variation and gene expression (http://www.sanger.ac. relatives yielded 1194 IgAN cases and 902 healthy controls uk/resources/software/genevar). The sequence variation recruited in the Renal Division of Peking University First and gene-expression profiling data were from lymphoblas- Hospital from 1997 to 2008 (8). All the cases were con- toid cell lines of 726 HapMap3 individuals. Another global firmed by renal biopsy, and all the controls were healthy map of the effects of polymorphism on gene expression in blood donors without indicators of renal disease. Quality 400 children from families recruited through a proband control was undertaken as described (8). Unexpected re- with asthma was also investigated to associate gene ex- latedness was excluded with a PLINK pi-hat cutoff of pression on the basis of imputed genotypes (45). 0.125. We
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