Systemic Lupus Erythematosus Loci Research Articles

The 330 risk loci known for systemic lupus erythematosus (SLE): a review

An in-depth literature review of up to 2023 reveals 330 risk loci found by genetic association at p ≤ 5 × 10−8, with systemic lupus erythematosus (SLE) in at least one study of 160 pertinent publications. There are 225 loci found in East Asian (EAS), 106 in European (EU), 11 in African-American (AA), 18 Mixed American (MA), and 1 in Egyptian ancestries. Unexpectedly, most of these associations are found to date at p ≤ 5 × 10−8 in a single ancestry. However, the EAS and EU share 40 risk loci that are independently established. The great majority of the identified loci [250 (75.8%) of 330] do not contain a variant that changes an amino acid sequence. Meanwhile, most overlap with known regulatory elements in the genome [266 (80.6%) of 330], suggesting a major role for gene regulation in the genetic mechanisms of SLE. To evaluate the pathways altered by SLE-associated variants, we generated gene sets potentially regulated by SLE loci that consist of the nearest genes, published attributions, and genes predicted by computational tools. The most useful insights, at present, suggest that SLE genetic mechanisms involve (1) the regulation of both adaptive and innate immune responses including immune cell activation and differentiation; (2) the regulation of production and response to cytokines, including type I interferon; (3) apoptosis; (4) the sensing and removal of immune complexes and apoptotic particles; and (5) immune response to infections, including Epstein–Barr Virus, and symbiont microorganisms. These mechanisms affected by SLE genes involve multiple cell types, including B cells/plasma cells, T cells, dendritic cells, monocytes/macrophages, natural killer cells, neutrophils, and endothelial cells. The genetics of SLE from GWAS data reveal an incredibly complex profusion of interrelated molecular processes and interacting cells participating in SLE pathogenesis, mostly unified in the molecular regulation of inflammatory responses. These genetic associations in lupus and affected molecular pathways not only give us an understanding of the disease pathogenesis but may also help in drug discoveries for SLE treatment.

A Multilayered Post-Genome-Wide Association Study Analysis Pipeline Defines Functional Variants and Target Genes for Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE), an autoimmune disease with incompletely understood etiology, has a strong genetic component. Although genome-wide association studies (GWASs) have revealed multiple SLE susceptibility loci and associated single-nucleotide polymorphisms (SNPs), the precise causal variants, target genes, cell types, tissues, and mechanisms of action remain largely unknown. Here, we report a comprehensive post-GWAS analysis using extensive bioinformatics, molecular modeling, and integrative functional genomic and epigenomic analyses to optimize fine-mapping. We compile and cross-reference immune cell-specific expression quantitative trait loci (cis- and trans-expression quantitative trait loci) with promoter capture high-throughput capture chromatin conformation (PCHi-C), allele-specific chromatin accessibility, and massively parallel reporter assay data to define predisposing variants and target genes. We experimentally validate a predicted locus using CRISPR/Cas9 genome editing, quantitative polymerase chain reaction, and Western blot. Anchoring on 452 index SNPs, we selected 9,931 high linkage disequilibrium (r2 > 0.8) SNPs and defined 182 independent non-human leukocyte antigen (HLA) SLE loci. The 3,746 SNPs from 143 loci were identified as regulating 564 unique genes. Target genes are enriched in lupus-related tissues and associated with other autoimmune diseases. Of these, 329 SNPs (106 loci) showed significant allele-specific chromatin accessibility and/or enhancer activity, indicating regulatory potential. Using CRISPR/Cas9, we validated reference SNP identifier 57668933 (rs57668933) as a functional variant regulating multiple targets, including SLE-risk gene ELF1 in B cells. We demonstrate and validate post-GWAS strategies for using multidimensional data to prioritize likely causal variants with cognate gene targets underlying SLE pathogenesis. Our results provide a catalog of significantly SLE-associated SNPs and loci, target genes, and likely biochemical mechanisms to guide experimental characterization.

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study

ObjectiveGenome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We...

Identification of Shared and Asian-Specific Loci for Systemic Lupus Erythematosus and Evidence for Roles of Type III Interferon Signaling and Lysosomal Function in the Disease: A Multi-Ancestral Genome-Wide Association Study.

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with differences in prevalence and severity among ancestral groups. This study was undertaken to identify novel genetic components, either shared by or distinct between Asian and European populations. Both trans-ancestral and ancestry-specific meta-analyses of genome-wide association studies (GWAS) for SLE were performed, involving 30,604 participants of European, Chinese, or Thai origin. Using public epigenomic data and expression quantitative trait loci, fine-mapping analyses were conducted to identify putative causal variants and genes for the newly identified loci. Performance of polygenic risk scores for the Thai cohort was evaluated by comparing different training data. A 1-bp deletion upstream of IFNLR1 was found to be associated with SLE, with the risk allele correlated with increased expression of IFNLR1. This gene encodes interferon-λ (IFNλ) receptor 1, providing evidence of a role of type III IFN signaling in SLE. An intronic variant in SLC29A3 was found to be associated with SLE in Asians only. The putative risk variant may modulate SLC29A3 expression in a monocyte-specific manner. SLC29A3 encodes a lysosomal nucleoside transporter, and subsequent analyses suggested that reduced lysosomal function and phagocytosis might be the mechanism underlying this association. Ancestry-shared loci in or near TAOK3, CHD9, CAMK1D, ATXN1, and TARBP1 and Asian-specific loci close to PEX2, FCHSD2, and TMEM116 also reached the genome-wide significant association with SLE. In addition, trans-ancestral meta-analysis was shown to be valuable in risk prediction for individuals without ancestry-matched data. In this study both shared and Asian-specific loci for SLE were identified, and functional annotation provided evidence of the involvement of increased type III IFN signaling and reduced lysosomal function in SLE.

Recent advances in understanding the genetic basis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a polygenic chronic autoimmune disease leading to multiple organ damage. A large heritability of up to 66% is estimated in SLE, with roughly 180 reported susceptibility loci that have been identified mostly by genome-wide association studies (GWASs) and account for approximately 30% of genetic heritability. A vast majority of risk variants reside in non-coding regions, which makes it quite challenging to interpret their functional implications in the SLE-affected immune system, suggesting the importance of understanding cell type-specific epigenetic regulation around SLE GWAS variants. The latest genetic studies have been highly fruitful as several dozens of SLE loci were newly discovered in the last few years and many loci have come to be understood in systemic approaches integrating GWAS signals with other biological resources. In this review, we summarize SLE-associated genetic variants in both the major histocompatibility complex (MHC) and non-MHC loci, examining polygenetic risk scores for SLE and their associations with clinical features. Finally, variant-driven pathogenetic functions underlying genetic associations are described, coupled with discussion about challenges and future directions in genetic studies on SLE.

Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups

Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.

Association of the Polymorphism rs13259960 in SLEAR With Predisposition to Systemic Lupus Erythematosus.

Genome-wide association studies have identified many susceptibility loci for systemic lupus erythematosus (SLE). However, most of these loci are located in noncoding regions of the genome. Long noncoding RNAs (lncRNAs) are pervasively expressed and have been reported to be involved in various diseases. This study aimed to explore the genetic significance of lncRNAs in SLE. A genome-wide survey of SLE risk variants in lncRNA gene loci was performed in Han Chinese subjects (4,556 with SLE and 9,451 healthy controls). The functional relevance of an SLE risk variant in one of the lncRNA genes was explored using biochemical and molecular cell biology analyses. In vitro loss-of-function and gain-of-function strategies were used to clarify the functional and phenotypic relevance of this SLE susceptibility lncRNA. Moreover, correlation of this lncRNA with the degree of apoptosis in the peripheral blood of SLE patients was evaluated. A novel SLE susceptibility locus in a lncRNA gene, designated SLEAR (for SLE-associated RNA), was identified at the single-nucleotide polymorphism rs13259960 (odds ratio 1.35, Pcombined = 1.03 × 10-11 ). The A>G variation at rs13259960, located in an intronic enhancer, was found to impair STAT1 recruitment to the enhancer that loops to the SLEAR promoter, resulting in decreased SLEAR production in peripheral blood mononuclear cells from patients with SLE (3 with the G/G genotype, 22 with A/G, and 103 with A/A at rs13259960; P = 0.0241). Moreover, SLEAR interacted with the RNA binding proteins interleukin enhancer binding factor 2, heterogeneous nuclear RNP F, and TATA-binding protein-associated factor 15, to form a complex for transcriptional activation of the downstream antiapoptotic genes. In addition, SLEAR regulated apoptosis of Jurkat cells in vitro, and its expression level was correlated with the degree of cell death in the peripheral blood of patients with SLE (r = 0.824, P = 2.15 × 10-8 ; n = 30). These findings suggest a mechanism by which the risk variant at rs13259960 modulates SLEAR expression and confers a predisposition to SLE. Taken together, these results may give insights into the etiology of SLE.

Mendelian randomization analysis revealed potential causal factors for systemic lupus erythematosus.

Genome-wide association studies (GWAS) have identified many loci for systemic lupus erythematosus (SLE). However, identification of functionally relevant genes remains a challenge. The aim of this study was to highlight potential causal genes for SLE in the GWAS loci. By applying Mendelian randomization (MR) methods, such as summary data-based MR (SMR), generalized SMR and MR pleiotropy residual sum and outlier, we identified DNA methylations in 15 loci and mRNA expression of 21 genes that were causally associated with SLE. The identified genes enriched in 14 specific KEGG pathways (e.g. SLE, viral carcinogenesis) and two GO terms (interferon-γ-mediated signaling pathway and innate immune response). Among the identified genes, UBE2L3 and BLK variants were significantly associated with UBE2L3 and BLK methylations and gene expressions, respectively. UBE2L3 was up-regulated in SLE patients in several types of immune cells. Methylations (e.g. cg06850285) and mRNA expression of UBE2L3 were causally associated with SLE. Methylation site cg09528494 and mRNA expression of BLK were causally associated with SLE. BLK single nucleotide polymorphisms that were significantly associated with SLE were strongly associated with plasma cathepsin B level. Deep analysis identified that plasma cathepsin B level was causally associated with SLE. In summary, this study identified hundreds of DNA methylations and genes as potential risk factors for SLE. Genetic variants in UBE2L3 gene might affect SLE by influencing gene expression. Genetic variants in BLK gene might affect SLE by influencing BLK gene expression and plasma cathepsin B protein level.

Genetic studies on systemic lupus erythematosus in East Asia point to population differences in disease susceptibility.

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with extreme clinical heterogeneity and significant differences between populations. East Asian populations are known to have higher prevalence and more severe clinical manifestations for SLE than Europeans. The difference could be the result of genetic and environmental factors, and the interactions between them. Thus, identifying genetic associations from diverse populations provides an opportunity to better understand the genetic architecture of this heterogeneous disease. It is also necessary to elucidate population differences and to apply the findings in future stratified treatment of the disease, with ethnicity likely a major factor to consider. Indeed, it has shown that there are significant differences between East Asians and European populations in several genetic loci for SLE. Genetic studies on SLE are very active in East Asian countries and there have been close collaborations among scientists in this region. Here, we document some work done in this region on SLE genetic research and discuss the aspect of population differences.

Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus

ObjectivesIKZF1 and IKZF3 (encoding transcription factors Ikaros and Aiolos) are susceptibility loci for systemic lupus erythematosus (SLE). The pharmacology of iberdomide (CC-220), a cereblon (CRBN) modulator targeting Ikaros and Aiolos,...

Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus

BackgroundSystemic lupus erythematosus (SLE) is a common systemic autoimmune disease with a complex genetic inheritance. Genome-wide association studies (GWAS) have significantly increased the number of significant loci associated with SLE risk. To date, however, established loci account for less than 30% of the disease heritability and additional risk variants have yet to be identified. Here we performed a GWAS followed by a meta-analysis to identify new genome-wide significant loci for SLE.MethodsWe genotyped a cohort of 907 patients with SLE (cases) and 1524 healthy controls from Spain and performed imputation using the 1000 Genomes reference data. We tested for association using logistic regression with correction for the principal components of variation. Meta-analysis of the association results was subsequently performed on 7,110,321 variants using genetic data from a large cohort of 4036 patients with SLE and 6959 controls of Northern European ancestry. Genetic association was also tested at the pathway level after removing the effect of known risk loci using PASCAL software.ResultsWe identified five new loci associated with SLE at the genome-wide level of significance (p < 5 × 10− 8): GRB2, SMYD3, ST8SIA4, LAT2 and ARHGAP27. Pathway analysis revealed several biological processes significantly associated with SLE risk: B cell receptor signaling (p = 5.28 × 10− 6), CTLA4 co-stimulation during T cell activation (p = 3.06 × 10− 5), interleukin-4 signaling (p = 3.97 × 10− 5) and cell surface interactions at the vascular wall (p = 4.63 × 10− 5).ConclusionsOur results identify five novel loci for SLE susceptibility, and biologic pathways associated via multiple low-effect-size loci.

837 Genome-wide association study identifies three novel susceptibility loci for systemic lupus erythematosus in Han Chinese

837 Genome-wide association study identifies three novel susceptibility loci for systemic lupus erythematosus in Han Chinese

Susceptibility Loci in C57BL/6 sle1, sle2 and sle3 Contain Genes that Alter Peripheral Selection of the CDR-H3 Sequences Enriched for Arginine

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by deposition of ds- DNA binding autoantibodies in various body organs. These antibodies result from failure to control the composition of the B cell repertoire. Development of optimum B cell repertoire depends on the amino acid composition and the physicochemical characteristics at the center of the antigen binding site, the third complementarity determining region heavy chain (CDR-H3). Repertoire control involves positive selection for hydrophilic amino acids such as tyrosine and negative selection of hydrophobic and charged amino acids, specifically those containing arginine within the CDR-H3. Anti-dsDNA antibodies present in SLE patients exist in healthy individuals but at low levels, since dsDNA-specific B cells are deleted from the repertoire, but amplified in SLE patients. These antibodies contain arginine residues in CDR-H3, especially at positions 99-102, where they are positioned to bind negatively charged phosphate groups on the DNA backbone. Three genomic intervals, namely sle1 on chromosome 1, sle2 on chromosome 4, and sle3 on chromosome 7, were found to be associated with SLE susceptibility. We hypothesized that development of ds-DNA binding antibodies in SLE might result from failure to control CDR-H3 amino acid composition. We proposed that the SLE congenic loci might have unique effects in allowing survival/expansion of B cells expressing these auto-reactive antibodies. Our strategy was to change the composition of CDR-H3 by altering the germline composition of the DH gene segments. We created a ΔD-iD altered allele enriched for arginine while depleted of tyrosine at positions 99-102. We then monitored the influence of different SLE loci on the development and maintenance of B cells bearing CDR-H3 arginine. These findings support our hypothesis that peripheral B cell selection is altered by the presence of sle congenic alleles, allowing passage of B cells able to produce autoreactive antibodies binding ds-DNA. These findings may help in developing therapeutics to suppress autoimmunity in SLE.

Exome-wide association study identifies four novel loci for systemic lupus erythematosus in Han Chinese population

ObjectivesSystemic lupus erythematosus (SLE) is a chronic autoimmune disease of considerable genetic predisposition. Genome-wide association studies have identified tens of common variants for SLE. However, the majority of them reside...

Novel linkage disequilibrium clustering algorithm identifies new lupus genes on meta-analysis of GWAS datasets

Systemic lupus erythematosus (SLE) is a complex disorder. Genetic association studies of complex disorders suffer from the following three major issues: phenotypic heterogeneity, false positive (type I error), and false negative (type II error) results. Hence, genes with low to moderate effects are missed in standard analyses, especially after statistical corrections. OASIS is a novel linkage disequilibrium clustering algorithm that can potentially address false positives and negatives in genome-wide association studies (GWAS) of complex disorders such as SLE. OASIS was applied to two SLE dbGAP GWAS datasets (6077 subjects; ∼0.75 million single-nucleotide polymorphisms). OASIS identified three known SLE genes viz. IFIH1, TNIP1, and CD44, not previously reported using these GWAS datasets. In addition, 22 novel loci for SLE were identified and the 5 SLE genes previously reported using these datasets were verified. OASIS methodology was validated using single-variant replication and gene-based analysis with GATES. This led to the verification of 60% of OASIS loci. New SLE genes that OASIS identified and were further verified include TNFAIP6, DNAJB3, TTF1, GRIN2B, MON2, LATS2, SNX6, RBFOX1, NCOA3, and CHAF1B. This study presents the OASIS algorithm, software, and the meta-analyses of two publicly available SLE GWAS datasets along with the novel SLE genes. Hence, OASIS is a novel linkage disequilibrium clustering method that can be universally applied to existing GWAS datasets for the identification of new genes.

Confirmation of five novel susceptibility loci for systemic lupus erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci.

We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta = 1.92 × 10-13, OR = 1.14), ATG16L2 (rs11235604, Pmeta = 8.87 × 10 -12, OR = 0.78), CCL22 (rs223881, Pmeta = 5.87 × 10-16, OR = 0.87), ANKS1A (rs2762340, Pmeta = 4.93 × 10-15, OR = 0.87) and RNASEH2C (rs1308020, Pmeta = 2.96 × 10-19, OR = 0.84) and co-located with annotated gene regulatory elements. The novel loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Most (56%) of the correlated (r2 > 0.8) SNPs from the 82 SLE loci were implicated in differential expression (9.81 × 10-198 < P < 5 × 10-3) of cis-genes. Transcription factor binding sites for p53, MEF2A and E2F1 were significantly (P < 0.05) over-represented in SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis.

Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry.

Genome-wide association studies (GWAS) in individuals of European ancestry identified a number of systemic lupus erythematosus (SLE) susceptibility loci using earlier versions of high-density genotyping platforms. Followup studies on suggestive GWAS regions using larger samples and more markers identified additional SLE loci in subjects of European descent. This multistage study was undertaken to identify novel SLE loci. In stage 1, we conducted a new GWAS of SLE in a North American case-control sample of subjects of European ancestry (n = 1,166) genotyped on Affymetrix Genome-Wide Human SNP Array 6.0. In stage 2, we further investigated top new suggestive GWAS hits by in silico evaluation and meta-analysis using an additional data set of subjects of European descent (>2,500 individuals), followed by replication of top meta-analysis findings in another data set of subjects of European descent (>10,000 individuals) in stage 3. As expected, our GWAS revealed the most significant associations at the major histocompatibility complex locus (6p21), which easily surpassed the genome-wide significance threshold (P < 5 × 10(-8)). Several other SLE signals/loci previously implicated in Caucasians and/or Asians were also confirmed in the stage 1 discovery sample, and the strongest signals were observed at 2q32/STAT4 (P = 3.6 × 10(-7)) and at 8p23/BLK (P = 8.1 × 10(-6)). Stage 2 meta-analyses identified a new genome-wide significant SLE locus at 12q12 (meta P = 3.1 × 10(-8)), which was replicated in stage 3. Our multistage study identified and replicated a new SLE locus that warrants further followup in additional studies. Publicly available databases suggest that this newly identified SLE signal falls within a functionally relevant genomic region and near biologically important genes.

Discovery of a novel genetic susceptibility locus on X chromosome for systemic lupus erythematosus.

IntroductionSystemic lupus erythematosus (SLE) is an autoimmune connective tissue disease affecting predominantly females. To discover additional genetic risk variants for SLE on the X chromosome, we performed a follow-up study of our previously published genome-wide association study (GWAS) data set in this study.MethodsTwelve single nucleotide polymorphisms (SNPs) within novel or unpublished loci with P-value < 1.00 × 10−02 were selected for genotype with a total of 2,442 cases and 2,798 controls(including 1,156 cases and 2,330 controls from central China, 1,012 cases and 335 controls from southern China and 274 cases and 133 controls from northern China) using Sequenom Massarry system. Associaton analyses were performed using logistic regression with sample region as a covariate through PLINK 1.07 software.ResultsCombined analysis in discovery and central validation dataset discovered a novel locus rs5914778 within LINC01420 associated with SLE at genome-wide significance (P = 1.00 × 10−08; odds ratio (OR) = 1.32). We also confirmed rs5914778 in the southern Chinese sample cohort (P = 5.31 × 10−05; OR = 1.51), and meta-analysis of the samples from the discovery, central and southern validations regions provided robust evidence for the association of rs5914778 (P = 5.26 × 10−12; OR = 1.35). However, this SNP did not show association with SLE in the northern sample (P = 0.33). Further analysis represent the association of northern was significantly heterogeneous compared to central and southern respectively.ConclusionsOur study increases the number of established susceptibility loci for SLE in Han Chinese population and has further demonstrated the important role of X-linked genetic risk variants in the pathogenesis of SLE in Chinese Han population.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0857-1) contains supplementary material, which is available to authorized users.

Association analyses confirm five susceptibility loci for systemic lupus erythematosus in the Han Chinese population.

IntroductionSystemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Currently, numerous genetic loci of SLE have been confirmed. Here we try to further explore additional genes contributing to SLE susceptibility in this study.MethodsForty nine single nucleotide polymorphisms (SNPs) with moderate-risk for SLE in previous study were genotyped in a large-scale replication study with a total of 3,522 cases and 8,252 controls using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate through PLINK 1.07 software.ResultsThis replication effort confirmed five reported SLE susceptibility loci reaching genome-wide levels of significance (Pmeta <5.00 × 10−08): TNFSF4 (rs1418190, odds ratio (OR) = 0.81, Pmeta = 1.08 × 10−08; rs4916219, OR = 0.80, Pmeta = 7.77 × 10−09), IRF8 (rs2934498, OR = 1.25, Pmeta = 4.97 × 10−09), miR-146a (rs2431697, OR = 0.69, Pmeta = 1.15 × 10−22), CD44 (rs2732547, OR = 0.82, Pmeta = 1.55 × 10−11), and TMEM39A (rs12494314, OR = 0.84, Pmeta = 1.01 × 10−09). Further logistic regression analysis indicated that the genetic effects within TNFSF4 detected in this study are independent from our previously reported signals.ConclusionsThis study increases the number of established susceptibility loci for SLE in Han Chinese population and highlights the contribution of multiple variants of modest effect. Although further studies will be required to identify the causal alleles within these loci, the findings make a significant step forward in our understanding of the genetic contribution to SLE in Chinese population.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0602-9) contains supplementary material, which is available to authorized users.

Association between PDCD1, CTLA4, and MECP2 gene polymorphisms and systemic lupus erythematosus in the Chinese Northern Han.

Systemic lupus erythematosus (SLE) is an autoimmune disease that results in chronic inflammation of different organ systems. Several susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes has yet to be determined. The programmed cell death 1 gene (PDCD1), the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene, and the methyl-CpG-binding protein 2 gene (MECP2) are considered to be the candidate genes associated with SLE. We analyzed the role of PDCD1, CTLA4, and MECP2 gene polymorphisms in Han patients suffering from SLE. Using a case-control study, 263 SLE patients and 263 healthy controls were collected from Chinese Northern Han people. Genomic DNA was prepared from peripheral blood leukocytes and the genotyping was performed using a polymerase chain reaction/ligase detection reaction assay. A statistically significant difference was observed in the rs2239464 and rs2075596 polymorphisms of MECP2 between SLE subjects and controls. The GG genotype in rs2239464 and the GG genotype in rs2075596 might protect against SLE. In contrast, no such association was found in the CTLA4 or PDCD1 polymorphisms. The rs2239464 and rs2075596 polymorphisms of MECP2 might play a significant role in the development of SLE in the Northern Han of China.