Susceptibility To Systemic Lupus Erythematosus Research Articles

Molecular basis for the disease-modifying effects of belimumab in systemic lupus erythematosus and molecular predictors of early response: blood transcriptome analysis implicates the innate immunity and DNA damage response pathways

ObjectivesBelimumab is a putative disease-modifying agent in systemic lupus erythematosus (SLE), yet the molecular underpinnings of its effects and the ability to predict early clinical response remain unexplored. To address...

Deciphering cell-specific genetic insights: Unraveling the immunogenetic landscape of systemic lupus erythematosus

Functional genes within genomic loci associated with systemic lupus erythematosus (SLE), as identified by genome-wide association studies, exhibit cell-specific characteristics. This study delves into the impact of genetic variants within SLE loci on gene expression in different types of immune cells, unraveling the complex interplay between genetics and immunopathogenesis. Through the integration of genetic association and single-cell transcriptomic sequencing data, we identified potential cell-specific susceptibility genes for SLE across diverse immune cell subsets. The single-cell eQTL analysis revealed 30,409 associations involving 3583 SLE-associated SNPs. These SNPs exhibited associations with expression levels of 147 genes across 14 distinct cell types. The single-cell summary data-based Mendelian randomization (SMR) analysis identified 119 significant associations between the expression levels of 44 genes and SLE. Notably, myeloid cells exhibited associations solely within the MHC region, while T, B, and natural killer cells showed associations with both MHC and non-MHC genes in relation to SLE. Analysis of single-cell transcriptomic data from 33 children SLE cases and 11 match controls (227,303 cells), as well as 7 adult SLE cases and 5 match controls (78,414 cells) highlights differential expression of key genes. Notably, genetic variants within HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, IRF7, IRF5, BLK and HLA-DPA1 play a pivotal role in mediating immune dysregulation in specific immune cell types. Our study contributes to a comprehensive understanding of the intricate relationships between genetics, gene expression and SLE susceptibility. The findings shed light on the cell-specific impacts of genetic variants within SLE-associated genomic loci.

Identification of RNA uridylation subtypes, and the prognostic and therapeutic value of RNA uridylation in systemic lupus erythematosus

The uridylation of 3′-RNA-a major process in epitranscriptomics- is catalyzed by terminal uridylyl transferases (TUTases), which are involved in multiple diseases and the immune response. Nonetheless, the role of TUTases in systemic lupus erythematosus (SLE) remains unknown. Here we identified increased level of MTPAP and ZCCHC6 and decreased level of PAPD5 and ZCCHC11 in SLE patients from Gene Expression Omnibus (GEO) GSE50772, GSE65391, and GSE121239. The random forest model was applied to screen 4 TUTase candidates (MTPAP, ZCCHC6, PAPD5, and ZCCHC11) to predict the susceptibility of SLE. A nomogram was constructed based on the 4 selected TUTase regulators. Decision curve analysis indicated that patients could benefit from the nomogram. Moreover, based on the 4 differentially expressed genes, individuals with SLE were divided into three patterns (Cluster A-C) using the consensus clustering method. Cluster B was enriched in adaptive immune cells, with the lowest TCE signature expression, manifesting a higher Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) than that in Cluster A and C. whereas, Cluster C was enriched in innate immune cells, with the highest T-cell exhaustion (TCE) signature expression, manifesting lower SLEDAI than that in Cluster B. Clinically, lupus nephritis (LN) patients manifested increased expression of MTPAP and ZCCHC6 and decreased expression of PAPD5 and ZCCHC11 in PBMCs using Quantitative Polymerase Chain Reaction (q-PCR). Immunohistochemistry (IHC) illustrated higher level of ZCCHC6 in the kidneys of LN patients than that in NC. In summary, TUTases could predict the occurrence of SLE and stratify patients based on their immune characteristics, eventually predicting the disease activity and guiding immune therapy.

Association Study of 3-untranslated region Haplotype of Human leukocyte antigen-G Gene with Lupus.

Background: Human leukocyte antigen-G (HLA-G) is a pivotal protein involved in immune regulation and tolerance, while systemic lupus erythematosus (SLE) is a multifaceted autoimmune condition influenced by genetic and environmental factors. Research indicates that variations and mutations in HLA-G may impact SLE development. Objective: This study aimed to explore the relationship between polymorphisms in the 3'-untranslated region (UTR) of the HLA-G gene and SLE. Methods: DNA from 100 SLE patients and 100 controls was analyzed using polymerase chain reaction to amplify the target sequence. Allele and genotype frequencies were determined, and haplotypes were assessed using Haploview v.4.2 software, with linkage disequilibrium calculated. Results: Findings revealed that the +2960 Ins allele was significantly linked to SLE as a risk factor, with the Del allele showing a protective effect. In addition, the +3010C allele and +3187A allele were significantly associated with SLE at both allele and genotype levels. The +3142 GG homozygote was notably linked to SLE at the genotype level. Haplotype analysis identified UTR-2 haplotypes as risk factors for SLE, whereas the UTR-1 haplotype was protective, shedding light on genetic factors influencing SLE risk. Conclusion: This study underscores the importance of HLA-G gene 3'-UTR polymorphisms in SLE susceptibility, suggesting their potential as diagnostic or therapeutic targets.

Assessing causal association of circulating micronutrients and systemic lupus erythematosus susceptibility: a Mendelian randomization study.

Previous studies showed the conflicting associations between circulating micronutrient levels and systemic lupus erythematosus (SLE). Therefore, we aimed to clarify the causal association between circulating micronutrient levels and the risk of SLE by two-sample Mendelian randomization (MR) analysis. 56 single nucleotide polymorphisms (SNPs) significantly associated with 14 circulating micronutrients (vitamin A, B6, B9, B12, C, D and E, phosphorus, calcium, magnesium, copper, iron, zinc, and selenium) in published genome-wide association studies (GWAS) were used as instrumental variables (IVs). And summary statistics related to SLE were obtained from the IEU OpenGWAS database. We used the MR Steiger test to estimate the possible causal direction between circulating micronutrients and SLE. In the MR analysis, inverse variance weighting (IVW) method and the Wald ratio was as the main methods., Moreover, the MR-Pleiotropy residuals and outliers method (MR-PRESSO), Cochrane's Q-test, MR-Egger intercept method and leave-one-out analyses were applied as sensitivity analyses. Additionally, we conducted a retrospective analysis involving the 20,045 participants from the Third National Health and Nutritional Examination Survey (NHANES III). Weight variables were provided in the NHANES data files. Univariate and multivariate logistic regression analyses were performed to determine the associations between circulating micronutrients and SLE. The MR estimates obtained from the IVW method revealed potential negative correlations between circulating calcium (OR: 0.06, 95% CI: 0.01-0.49, P = 0.009), iron levels (OR: 0.63, 95% CI: 0.43-0.92, P = 0.016) and the risk of SLE. The results remained robust, even under various pairs of sensitivity analyses. Our retrospective analysis demonstrated that the levels of vitamin D, serum total calcium, and serum iron were significantly lower in SLE patients (N = 40) when compared to the control group (N = 20,005). Multivariate logistic regression analysis further established that increased levels of vitamin D and serum total calcium served as protective factors against SLE. Our results provided genetic evidence supporting the potential protective role of increasing circulating calcium in the risk of SLE. Maintaining adequate levels of calcium may help reduce the risk of SLE.

Biochemical study of ZNF76 rs10947540 and SCUBE3 rs1888822 single nucleotide polymorphisms in the Egyptian patients with systemic lupus Erythematosus

ABSTRACT Systemic lupus erythematosus (SLE) is a common autoimmune disease marked by the formation of apoptotic debris and the presence of autoantibodies that target nuclear components. At this moment, the actual cause of SLE is uncertain. Genetic variables have been well proven to have a significant role in the propensity of SLE. This study aimed to investigate the effect of (ZNF76) rs (10947540) and (SCUBE) rs (1888822) gene polymorphism in patients with systemic lupus erythematosus. A case control study has been carried out at Medical Biochemistry & Molecular biology and Rheumatology unit of Internal Medicine Departments, Faculty of Medicine, Menoufia University, Egypt, for 1-year duration between 1 June 2022 and 1 June 2023. Sixty patients were females (75%) and twenty patients were males (25%). Their ages ranged from 19 to 53 years. Their disease durations ranged from 7 months to 20 years. The findings indicated that the TC genotype of the ZNF76 rs10947540 gene increases the risk of SLE by 2.274-fold, while the dominant TC + CC increases the risk by 2.472-fold, and the C allele increases the risk by 2.115-fold. Additionally, the results showed that the TT genotype of the SCUBE3 rs1888822 gene increases the risk of SLE by 3.702-fold, the dominant GT + TT increases the risk by 2.304-fold, and the T allele increases the risk by 2.089-fold, while the GT genotype increases the risk by 1.918-fold. The study revealed significant associations between the genotypes of these polymorphisms and certain clinical parameters in SLE patients. These findings highlight the potential genetic contributions to SLE susceptibility and its clinical manifestations, providing valuable insights for future research and potential personalized approaches to the management of this complex autoimmune disease.

Air Pollution, Genetic Susceptibility, and Risk of Incident Systemic Lupus Erythematosus: A Prospective Cohort Study.

There are few existing studies that investigate the risk of systemic lupus erythematosus (SLE) associated with long-term exposure to air pollutants. This study aimed to explore associations between long-term exposure to air pollutants and incident SLE and further evaluate interactions and joint effects of genetic risk and air pollutants. A total of 459,815 participants were included from UK Biobank. The concentrations of air pollutants (fine particulate matter with diameter ≤2.5 μm [PM2.5], particulate matter diameter ≤10 μm [PM10], nitrogen dioxide [NO2], and nitrogen oxides [NOx]) were estimated by land-use regression model. We applied Cox proportional hazards model to explore linkages of air pollutants and incident SLE. The polygenic risk score (PRS) was used for further assessing the interactions and joint effects of genetic risk and air pollutants. A total of 399 patients with SLE were identified during a median follow-up of 11.77 years. There were positive associations between air pollutant exposure and incident SLE, as the adjusted hazard ratios were 1.18 (95% confidence interval [95% CI] 1.06-1.32), 1.23 (1.10-1.39), 1.27 (1.14-1.41), and 1.13 (1.03-1.23) for each interquartile range increase in PM2.5, PM10, NO2, and NOx, respectively. Moreover, participants with high genetic risk and high air pollution exposure had the highest risk of incident SLE compared with those with low genetic risk and low air pollution exposure (adjusted hazard ratio: PM2.5, 4.16 [95% CI 2.67-6.49]; PM10, 5.31 [95% CI 3.30,-8.55]; NO2, 5.61 [95% CI 3.45-9.13]; and NOx, 4.80 [95% CI 3.00-7.66]). There was a significant multiplicative interaction between NO2 and PRS. Long-term exposure to air pollutants (PM2.5, PM10, NO2, and NOx) may increase the risk of developing SLE.

Association of Serum Programmed Cell Death Protein 1 (PD-1) and Gene Polymorphism with Some Valid Predictors for Systemic Lupus Erythematosus (SLE) Patients in Basra Province, Iraq

INTRODUCTION: Systemic Lupus Erythematosus (SLE) is a systematic autoimmune disorder characterized by the production of autoantibodies against nuclear antigens and inflammation initiation. We aimed to examine the correlation between IL-18, IL-37, and PD-1, and the potential link between polymorphisms in the PD-1 gene located in intron-4 and the susceptibility to SLE. MATERIALS AND METHODS: This cross-sectional study included 43 SLE and 53 healthy individuals. Blood samples were obtained and underwent biochemical examination. The polymorphisms were screened by amplifying the intron-4 of the PD-1 gene using particular primers and then verified through sequencing. RESULTS: Our findings demonstrated statistically significant positive correlations between IL-18, IL-37, and PD-1, while the AUC of the ROC curve is 0.985, 0.968, and 0.940, and cut-off concentration is ≥132.87, ≥62.98, and ≥169.02, respectively. Moreover, two separate SNPs (rs6705653 and rs41386349) were discovered within intron-4 of the PD-1 gene. The genotype AA of the +7499 (G/A) SNP was significantly related with an increased risk of SLE (OR=3.11, 95%CI=1.52–5.94, p-value=0.031). Additionally, the A allele was identified as a risk allele (OR=1.59, 95%CI=1.09–2.31, p-value=0.043). Nevertheless, our study didn’t find any noteworthy connection between the allele and genotype of the +7209 (C/T) polymorphism region of the PD-1 gene frequencies and the susceptibility to SLE. CONCLUSION: IL-18, IL-37, and PD-1 may play significant roles in SLE immune responses and processes. Furthermore, the sequencing examination of intron-4 within the PD-1 gene demonstrated a noteworthy correlation between the A allele and the AA genotypes of PD-1 +7499 (G/A) SNP presence with the increased SLE susceptibility.

Exploring the Relationship between ACE Gene Variants and Systemic Lupus Erythematosus Susceptibility in the Hainan Population through Genetic Association Analysis.

The purpose of this study was to determine the association between single nucleotide polymorphisms (SNPs) at the rs4331, rs4341, and rs4351 loci of the angiotensinconverting enzyme (ACE) gene and genetic susceptibility to systemic lupus erythematosus (SLE) in the Hainan population. This study involved a total of 428 participants, with 214 individuals diagnosed with SLE and an equal number of healthy controls. The SNaPshot sequencing technique was used to determine the base sequences at the ACE gene rs4331, rs4341, and rs4351 loci in the study subjects. Logistic regression was employed to compare the frequency distribution of genotypes and allele frequencies at each locus between the case group and the control group. HaploView 4.2 software was used to analyze the relationship between haplotypes at each locus and genetic susceptibility to SLE. The GG genotype and G allele frequency at the rs4341 locus were higher in the case group compared to the control group. In the rs4341 recessive model, carriers of the GG genotype were more likely to develop SLE compared to carriers of the CG+CC genotype (OR = 1.889, 95% CI: 1.195-2.988, P = 0.006). In the rs4351 overdominant model, carriers of the AC genotype had an increased risk of developing SLE compared to carriers of the AA+CC genotype (OR = 1.514, 95% CI: 1.033-2.219, P = 0.033). The rs4341 and rs4351 loci exhibited linkage disequilibrium, and the CA haplotype (OR = 0.630, 95% CI: 0.481-0.826, P = 0.001) was a protective factor against SLE. The GA haplotype (OR = 2.849, 95% CI: 1.901-4.270, P < 0.01) and the CC haplotype (OR = 2.309, 95% CI: 1.210-4.405, P = 0.009) were risk factors for genetic susceptibility to SLE in the Hainan population. The rs4341 locus of the ACE gene is associated with genetic susceptibility to SLE in the Hainan population.

KLF2 enhancer variant rs4808485 increases lupus risk by modulating inflammasome machinery and cellular homoeostasis

ObjectiveA recent genome-wide association study linked KLF2 as a novel Asian-specific locus for systemic lupus erythematosus (SLE) susceptibility. However, the underlying causal functional variant(s), cognate target gene(s) and genetic mechanisms...

Human and Murine Toll-like Receptor-Driven Disease in Systemic Lupus Erythematosus.

The pathogenesis of systemic lupus erythematosus (SLE) is linked to the differential roles of toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. TLR7 overexpression or gene duplication, as seen with the Y-linked autoimmune accelerator (Yaa) locus or TLR7 agonist imiquimod, correlates with increased SLE severity, and specific TLR7 polymorphisms and gain-of-function variants are associated with enhanced SLE susceptibility and severity. In addition, the X-chromosome location of TLR7 and its escape from X-chromosome inactivation provide a genetic basis for female predominance in SLE. The absence of TLR8 and TLR9 have been shown to exacerbate the detrimental effects of TLR7, leading to upregulated TLR7 activity and increased disease severity in mouse models of SLE. The regulatory functions of TLR8 and TLR9 have been proposed to involve competition for the endosomal trafficking chaperone UNC93B1. However, recent evidence implies more direct, regulatory functions of TLR9 on TLR7 activity. The association between age-associated B cells (ABCs) and autoantibody production positions these cells as potential targets for treatment in SLE, but the lack of specific markers necessitates further research for precise therapeutic intervention. Therapeutically, targeting TLRs is a promising strategy for SLE treatment, with drugs like hydroxychloroquine already in clinical use.

Polygenic Risk Score Predicts Earlier-Onset Adult Systemic Lupus Erythematosus and First-Year Renal Diseases in a Taiwanese Cohort

ObjectivesThis study aimed to develop a predictive model using polygenic risk score (PRS) to forecast renal outcomes for adult systemic lupus erythematosus (SLE) in a Taiwanese population.MethodsPatients with SLE (n=2782)...

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.

IKZF1 rs4132601 and rs11978267 gene polymorphisms and paediatric systemic lupus erythematosus; relation to lupus nephritis.

The demographic factors, the socioeconomic status and the ethnicity of populations are important players that determine the incidence, the prevalence and the spectrum of systemic lupus erythematosus (SLE) clinical presentations in different populations. Therefore, the purpose of the present research was to investigate the possible association between the Ikaros family zinc finger 1 gene (IKZF1) rs4132601 and rs11978267 single nucleotide polymorphisms (SNPs) and SLE susceptibility and clinical presentations including lupus nephritis (LN) among Egyptian paediatric patients. After DNA extraction from Ethylenediaminetetraacetic acid (EDTA) blood samples for 104 paediatric SLE (pSLE) patients and 286 healthy controls, the investigated SNPs (IKZF1 rs4132601 and rs11978267) were genotyped using TaqMan-Real-time Polymerase chain reaction (PCR). The G allele, GG and GT genotypes of IKZF1 rs4132601 were associated with pSLE (pc<.001, OR 2.97, 3.2 and 2.25, respectively). The GG and GA haplotype were more frequent in pSLE patients than other haplotypes (pc<.001, OR 3.47 and pc=.004, OR=2.8, respectively). The studied SNPs have no impact on the distinctive features of pSLE. The rs4132601 TG genotype was significantly associated with proliferative LN (pc=.03) The IKZF1 rs4132601 can be considered a risk factor for SLE in the cohort of Egyptian children. The TG genotype of the IKZF1 rs4132601 may predispose to proliferative LN.

Optimizing Warfarin use in Egyptian patients with Autoimmune Diseases – Genetic and Clinical Related Factors

Introduction: Over the last Century, Thousands of studies were conducted to highlight the factors affecting warfarin efficacy and toxicity. Many of these studies had major limitations because they focused only on one or a few factors. Objectives: to determine the effect of 14 different clinical and genetic factors on the clinical outcomes (efficacy and toxicity) of warfarin in Egyptian patients with autoimmune diseases. The secondary objective was detecting the association between genetic polymorphisms of VKORC1 (rs 9923231) and systemic lupus erythematosus (SLE) susceptibility in the Egyptian population. Methods: after signing a consent form, 150 patients were included in the study from Kasr Aleiny Hospital, Cairo University. All medical records were reviewed to extract the effect of age, sex, diagnoses, genotypes, warfarin-drug interactions, and all patients' comorbidities on warfarin's efficacy and toxicity. The average warfarin doses, INR, (No. of times)/total times of INR within the therapeutic range, differences between the maximum and minimum INR values, the addition of enoxaparin and discontinuing warfarin and shifting to Rivaroxaban, and bleeding episodes were determined. Results: all the studied factors had clinical and statistical significance on the clinical outcomes. The T allele was associated with treatment failure and a shift to rivaroxaban, a higher risk of bleeding and SLE. Conclusions: Awareness of the effect of the factors addressed in this study is mandatory for the assessment of warfarin efficacy and toxicity for each patient. Further studies are essential in other specialties because different warfarin-drug interactions may be detected, with other comorbidities and on different genes.

Large-scale DNA sequencing identifies rare variants associated with Systemic Lupus Erythematosus susceptibility in known risk genes

The identification of rare genetic variants associated to Systemic Lupus Erythematosus (SLE) could also help to understand the pathogenic mechanisms at the basis of the disease. In this study we have analyzed a cohort of 200 Italian SLE patients in order to explore the rare protein-coding variants in five genes (TNFAIP3, STAT4, IL10, TRAF3IP2, and HCP5) already investigated for commons variants found associated in our previous studies.Genomic DNA of 200 SLE patients was sequenced by whole exome sequencing. The identified variants were filtered by frequency and evaluated by in silico predictions. Allelic association analysis was performed with standard Fisher’s exact test.Introducing a cutoff at MAF < 0.01, a total of 19 rare variants were identified. Seven of these variants were ultra-rare (MAF < 0.001) and six were absent in the GnomAD database. For TNFAIP3 gene, the variant c.A1939C was observed in 4 SLE patients and it is located in a region enriched in phosphorylation sites and affects the predict affinity of specific kinases. In TRAF3IP2 gene, we observed 5 different rare variants, including the novel variant c.G410A, located in the region that mediates interaction with TRAF6, and therefore a possible risk factor for SLE development. In STAT4 gene, we identified 6 different rare variants. Among these, three missense variants decrease the stability of this protein. Moreover, 3 novel rare variants were detected in 3 SLE patients. In particular, c.A767T variant was predicted as damaging by six prediction tools.Concluding, we have observed that even in genes whose common variability is associated with SLE susceptibility, it is possible to identify rare variants that could have a strong effect in the disease development and could therefore allow a better understanding of the functional domain involved.

Attenuation of HOIL-1L ligase activity promotes systemic autoimmune disorders by augmenting linear ubiquitin signaling.

Linear ubiquitin chains, which are generated specifically by the linear ubiquitin assembly complex (LUBAC) ubiquitin ligase, play crucial roles in immune signaling, including NF-κB activation. LUBAC comprises catalytic large isoform of heme-oxidized iron regulatory protein 2 ubiquitin ligase 1 (HOIL-1L) interacting protein (HOIP), accessory HOIL-1L, and SHANK-associated RH domain-interacting protein (SHARPIN). Deletion of the ubiquitin ligase activity of HOIL-1L, an accessory ligase of LUBAC, augments LUBAC functions by enhancing LUBAC-mediated linear ubiquitination, which is catalyzed by HOIP. Here, we show that HOIL-1L ΔRING1 mice, which exhibit augmented LUBAC functions upon loss of the HOIL-1L ligase, developed systemic lupus erythematosus (SLE) and Sjögren's syndrome in a female-dominant fashion. Augmented LUBAC activity led to hyperactivation of both lymphoid and myeloid cells. In line with the findings in mice, we sought to identify missense single nucleotide polymorphisms/variations of the RBCK1/HOIL-1L gene in humans that attenuate HOIL-1L ligase activity. We found that the R464H variant, which is encoded by rs774507518 within the RBCK1/HOIL-1L gene, attenuated HOIL-1L ligase activity and augmented LUBAC-mediated immune signaling, including that mediated by Toll-like receptors. We also found that rs774507518 was enriched significantly in patients with SLE, strongly suggesting that RBCK1/HOIL-1L is an SLE susceptibility gene and that augmented linear ubiquitin signaling generated specifically by LUBAC underlies the pathogenesis of this prototype systemic autoimmune disease.

Causal association between systemic lupus erythematosus and the risk of migraine: A Mendelian randomization study.

Numerous studies have found that patients with systemic lupus erythematosus (SLE) often have comorbid headache, especially migraine. However, the causal relationship between genetically determined SLE and migraine risk remains unclear. Therefore, we conducted a Mendelian randomization (MR) study to explore this causal association. Genome-wide association studies (GWAS) provided the instrumental variables. We selected summary data from GWAS of SLE as exposure (5201 SLE patients and 9066 controls). Both outcome GWAS data were from the Finnish Gene GWAS, including migraine with aura, migraine with aura and triptan purchases, and migraine without aura. The main MR approach was inverse-variance weighted. Pleiotropy and heterogeneity were detected using the MR pleiotropy residual sum and outlier, MR-Egger intercept test, leave-one-out analysis, and Cochran's Q test. There was a significant association between genetically predicted SLE susceptibility and increased risk of migraine with aura [odds ratio (OR)=1.05, 95% confidence interval (CI)=1.02-1.08, p=.001]. The result was consistent when the outcome was migraine with aura and triptan purchases [OR=1.05, 95% CI=1.02-1.08, p=.001]. However, we found no association between SLE and migraine without aura. Our MR study showed no pleiotropy or heterogeneity. Our study indicates that genetic susceptibility to SLE increases the incidence of migraine with aura but not migraine without aura. It is necessary for the routine evaluation and early recognition of migraine in patients with SLE in clinical settings.

Identification of m6A-Related Biomarkers in Systemic Lupus Erythematosus: A Bioinformation-Based Analysis.

Systemic Lupus Erythematosus (SLE), a prototypical autoimmune disorder, presents a challenge due to the absence of reliable biomarkers for discerning organ-specific damage within SLE. A growing body of evidence underscores the pivotal involvement of N6-methyladenosine (m6A) in the etiology of autoimmune conditions. The datasets, which primarily encompassed the expression profiles of m6A regulatory genes, were retrieved from the Gene Expression Omnibus (GEO) repository. The optimal model, selected from either Random Forest (RF) or Support Vector Machine (SVM), was employed for the development of a predictive nomogram model. To identify pivotal genes associated with SLE, a comprehensive screening process was conducted utilizing LASSO, SVM-RFE, and RF techniques. Within the realm of SLE susceptibility, Weighted Gene Co-expression Network Analysis (WGCNA) was harnessed to delineate relevant modules and hub genes. Additionally, MeRIP-qPCR assays were performed to elucidate key genes correlated with m6A targets. Furthermore, a Mendelian randomization study was conducted based on genome-wide association studies to assess the causative influence of MMP9 on ischemic stroke (IS), which is not only a severe cerebrovascular event but also a common complication of SLE. Twelve m6A regulatory genes was identified, demonstrating statistical significance (p < 0.05) and utilized for constructing a nomogram model using the RF algorithm. EPSTI1, USP18, HP, and MMP9, as the hub genes, were identified. MMP9 uniquely correlates with m6A modification and was causally linked to an increased risk of IS, as indicated by our inverse variance weighting analysis showing an odds ratio of 1.0134 (95% CI=1.0004-1.0266, p = 0.0440). Our study identified twelve m6A regulators, shedding light on the molecular mechanisms underlying SLE risk genes. Importantly, our analysis established a causal relationship between MMP9, a key m6A-related gene, and ischemic stroke, a common complication of SLE, thereby providing critical insights for presymptomatic diagnostic approaches.

The functional TNFAIP3 rs2230926T/G (Phe127Cys) variant confers risk to systemic lupus erythematosus in a Latin American population

TNFAIP3 is a classical systemic lupus erythematosus (SLE)-associated risk locus identified by genome-wide association studies (GWASs) and replicated by candidate gene association studies primarily in Caucasians and Asians. However, in Latin American populations, its role on SLE susceptibility is not known. We conducted a case-control study to evaluate whether the TNFAIP3 rs2230926T/G (Phe127Cys) variant is associated with risk of developing SLE in a cohort of Mexican patients. The TNFAIP3 rs2230926T/G variant was analyzed in 561 patients with SLE and 499 control subjects, using TaqMan probes. We found that the G allele was associated with susceptibility to SLE under the allelic (OR 2.09, p = 0.005) and genotypic (OR 2.14, p = 0.004) models. In conclusion, our results show that TNFAIP3 rs2230926T/G is a risk factor for the development of SLE in the Mexican population.