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OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease resulting in debilitating clinical manifestations that vary in severity by race and ethnicity with a disproportionate burden in African American, Mestizo, and Asian populations compared with populations of European descent. Differences in global and local genetic ancestry may shed light on the underlying mechanisms contributing to these disparities, including increased prevalence of lupus nephritis, younger age of symptom onset, and presence of autoantibodies. METHODS: A total of 1,139 European, African American, and Mestizos patients with SLE were genotyped using the Affymetrix LAT1 World array. Global ancestry proportions were estimated using ADMIXTURE, and local ancestry was estimated using RFMIXv2.0. We investigated associations between lupus nephritis, age at onset, and autoantibody status with both global and local ancestry proportions within the Major Histocompatibility Complex region. RESULTS: Our results showed small effect sizes that did not meet the threshold for statistical significance for global or local ancestry proportions in either African American or Mestizo patients with SLE who presented with the clinical manifestations of interest compared with those who did not. CONCLUSION: These findings suggest that local genetic ancestry within the Major Histocompatibility Complex region is not a major contributor to these SLE manifestations among patients with SLE from admixed populations.

The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10−8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10−8). A total of 113 variants were associated with survival at P-value < 1.0 × 10−5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways. [ABSTRACT FROM AUTHOR]

The article is a response to a letter discussing the effectiveness of a web application called MyPROSLE in classifying patients with lupus nephritis. The authors clarify that MyPROSLE is meant to provide additional information for clinical decisions, not replace standard diagnostic procedures. They address concerns raised in the letter and provide detailed explanations and analysis of MyPROSLE's performance. The authors also discuss the impact of incorporating healthy samples in the analysis and highlight the need for considering multiple performance metrics. They emphasize that MyPROSLE should only be used for research purposes and provide data availability and funding information. [Extracted from the article]

Objective Methods Results Conclusion Primary antiphospholipid syndrome (PAPS) is a rare autoimmune disease characterized by the presence of antiphospholipid antibodies and the occurrence of thrombotic events and pregnancy complications. Our study aimed to identify novel genetic susceptibility loci associated with PAPS.We performed a genome‐wide association study comprising 5,485 individuals (482 affected individuals) of European ancestry. Significant and suggestive independent variants from a meta‐analysis of approximately 7 million variants were evaluated for functional and biological process enrichment. The genetic risk variability for PAPS in different populations was also assessed. Hierarchical clustering, Mahalanobis distance, and Dirichlet Process Mixtures with uncertainty clustering methods were used to assess genetic similarities between PAPS and other immune‐mediated diseases.We revealed genetic associations with PAPS in a regulatory locus within the HLA class II region near HLA‐DRA and in STAT1‐STAT4 with a genome‐wide level of significance; 34 additional suggestive genetic susceptibility loci for PAPS were also identified. The disease risk allele near HLA‐DRA is associated with overexpression of HLA‐DRB6, HLA‐DRB9, HLA‐DQA2, and HLA‐DQB2 in immune cells, vascular tissue, and nervous tissue. This association is independent of the association between PAPS and HLA‐DRB1*1302. Functional analyses highlighted immune‐related pathways in PAPS‐associated loci. The comparison with other immune‐mediated diseases revealed a close genetic relatedness to neuromyelitis optica, systemic sclerosis, and Sjögren syndrome, suggesting co‐localized causal variations close to STAT1‐STAT4, TNPO3, and BLK.This study represents a comprehensive large‐scale genetic analysis for PAPS and provides new insights into the genetic basis and pathophysiology of this rare disease. [ABSTRACT FROM AUTHOR]

This study aimed at defining the role of the B-cell adaptor protein BANK1 in the appearance of age-associated B cells (ABCs) in two SLE mouse models (TLR7.tg6 and Imiquimod-induced mice), crossed with Bank1-/- mice. The absence of Bank1 led to a significant reduction in ABC levels, also affecting other B cell populations. To gain deeper insights into their differentiation pathway and the impact of Bank1 on B cell populations, a single-cell transcriptome assay was performed. In the TLR7.tg6 model, we identified 10 clusters within B cells, including an ABC-specific cluster which was decreased in Bank1-deficient mice. In its absence, ABCs exhibited an anti-inflammatory gene expression profile, while being pro-inflammatory in Bank1-sufficient lupus mice. Trajectory analyses revealed that ABCs originated from marginal zone and memory-like B cells, ultimately acquiring transcriptional characteristics associated with atypical memory cells and long-lived plasma cells. Also, Bank1 deficiency normalized the presence of naïve B cells, which were nearly absent in lupus mice. Interestingly, Bank1 deficiency significantly reduced a distinct cluster containing IFN-responsive genes. These findings underscore the critical role of Bank1 in ABC development, impacting early B cell stages towards ABC differentiation, and the presence of IFN-stimulated gene-containing B cells, both populations determinant for autoimmunity.

The heterogeneity of systemic lupus erythematosus (SLE) can be explained by epigenetic alterations that disrupt transcriptional programs mediating environmental and genetic risk. This study evaluated the epigenetic contribution to SLE heterogeneity considering molecular and serological subtypes, genetics and transcriptional status, followed by drug target discovery. We performed a stratified epigenome-wide association studies of whole blood DNA methylation from 213 SLE patients and 221 controls. Methylation quantitative trait loci analyses, cytokine and transcription factor activity - epigenetic associations and methylation-expression correlations were conducted. New drug targets were searched for based on differentially methylated genes. In a stratified approach, a total of 974 differential methylation CpG sites with dependency on molecular subtypes and autoantibody profiles were found. Mediation analyses suggested that SLE-associated SNPs in the HLA region exert their risk through DNA methylation changes. Novel genetic variants regulating DNAm in disease or in specific molecular contexts were identified. The epigenetic landscapes showed strong association with transcription factor activity and cytokine levels, conditioned by the molecular context. Epigenetic signals were enriched in known and novel drug targets for SLE. This study reveals possible genetic drivers and consequences of epigenetic variability on SLE heterogeneity and disentangles the DNAm mediation role on SLE genetic risk and novel disease-specific meQTLs. Finally, novel targets for drug development were discovered., (© 2024. The Author(s).)

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by diverse clinical manifestations affecting multiple organs and systems. The understanding of genetic factors underlying the various manifestations of SLE has evolved considerably in recent years. This review provides an overview of the genetic implications in some of the most prevalent manifestations of SLE, including renal involvement, neuropsychiatric, cutaneous, constitutional, musculoskeletal, and cardiovascular manifestations. We discuss the current state of knowledge regarding the genetic basis of these manifestations, highlighting key genetic variants and pathways implicated in their pathogenesis. Additionally, we explore the clinical implications of genetic findings, including their potential role in risk stratification, prognosis, and personalized treatment approaches for patients with SLE. Through a comprehensive examination of the genetic landscape of SLE manifestations, this review aims to provide insights into the underlying mechanisms driving disease heterogeneity and inform future research directions in this field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To unveil biological milieus underlying low disease activity (LDA) and remission versus active systemic lupus erythematosus (SLE)., Methods: We determined differentially expressed pathways (DEPs) in SLE patients from the PRECISESADS project (NTC02890121) stratified into patients fulfilling and not fulfilling the criteria of (1) Lupus LDA State (LLDAS), (2) Definitions of Remission in SLE remission, and (3) LLDAS exclusive of remission., Results: We analysed data from 321 patients; 40.8% were in LLDAS, and 17.4% in DORIS remission. After exclusion of patients in remission, 28.3% were in LLDAS. Overall, 604 pathways differed significantly in LLDAS versus non-LLDAS patients with an false-discovery rate-corrected p (q)<0.05 and a robust effect size (dr)≥0.36. Accordingly, 288 pathways differed significantly between DORIS remitters and non-remitters (q<0.05 and dr≥0.36). DEPs yielded distinct molecular clusters characterised by differential serological, musculoskeletal, and renal activity. Analysis of partially overlapping samples showed no DEPs between LLDAS and DORIS remission. Drug repurposing potentiality for treating SLE was unveiled, as were important pathways underlying active SLE whose modulation could aid attainment of LLDAS/remission, including toll-like receptor (TLR) cascades, Bruton tyrosine kinase (BTK) activity, the cytotoxic T lymphocyte antigen 4 (CTLA-4)-related inhibitory signalling, and the nucleotide-binding oligomerization domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome pathway., Conclusions: We demonstrated for the first time molecular signalling pathways distinguishing LLDAS/remission from active SLE. LLDAS/remission was associated with reversal of biological processes related to SLE pathogenesis and specific clinical manifestations. DEP clustering by remission better grouped patients compared with LLDAS, substantiating remission as the ultimate treatment goal in SLE; however, the lack of substantial pathway differentiation between the two states justifies LLDAS as an acceptable goal from a biological perspective., Competing Interests: Competing interests: IP has received research funding and/or honoraria from Amgen, AstraZeneca, Aurinia, Elli Lilly, Gilead, GlaxoSmithKline, Janssen, Novartis, Otsuka, and Roche., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Clinical studies are conducted to better understand the pathological mechanism of diseases and to find biomarkers associated with disease activity, drug response, or outcome prediction. Mass cytometry (MC) is a high-throughput single-cell technology that measures hundreds of cells per second with more than 40 markers per cell. Thus, it is a suitable tool for immune monitoring and biomarker discovery studies. Working in translational and clinical settings requires a careful experimental design to minimize, monitor, and correct the variations introduced during sample collection, preparation, acquisition, and analysis. In this review, we will focus on these important aspects of MC-related experiments and data curation in the context of translational clinical research projects., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)