A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus

ObjectiveSystemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations.MethodsWe newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations.ResultsWe identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10−8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=−0.242) and non-albumin protein (rg=0.238).ConclusionThis study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

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Brief Report: Large-scale analysis of tumor necrosis factor α levels in systemic lupus erythematosus

Arthritis & Rheumatism ◽

10.1002/art.34483 ◽

2012 ◽

Vol 64 (9) ◽

pp. 2947-2952 ◽

Cited By ~ 43

Author(s):

Corinna E. Weckerle ◽

Dorothy Mangale ◽

Beverly S. Franek ◽

Jennifer A. Kelly ◽

Marissa Kumabe ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Tumor Necrosis ◽

Large Scale ◽

Tumor Necrosis Factor Α ◽

Scale Analysis ◽

Systemic Lupus ◽

Large Scale Analysis ◽

Factor Α ◽

Necrosis Factor

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Variation in the ICAM1–ICAM4–ICAM5 locus is associated with systemic lupus erythematosus susceptibility in multiple ancestries

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2011-201110 ◽

2012 ◽

Vol 71 (11) ◽

pp. 1809-1814 ◽

Cited By ~ 43

Author(s):

Kwangwoo Kim ◽

Elizabeth E Brown ◽

Chan-Bum Choi ◽

Marta E Alarcón-Riquelme ◽

Jennifer A Kelly ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Large Scale ◽

Meta Analysis ◽

Gene Interaction ◽

Nucleotide Polymorphisms ◽

Systemic Lupus ◽

Intracellular Adhesion Molecule ◽

Single Marker ◽

Genetic And Environmental Factors

ObjectiveSystemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin αM (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM.MethodsThe authors examined several markers in the ICAM1–ICAM4–ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case–control study of 17 481 unrelated participants from four ancestry populations. The single-marker association and gene–gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed.ResultsThe A-allele of ICAM1–ICAM4–ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (ORmeta=1.16, 95% CI 1.11 to 1.22; p=4.88×10−10 and ORmeta=1.67, 95% CI 1.55 to 1.79; p=3.32×10−46, respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10−5).ConclusionThese findings are the first to suggest that an ICAM–integrin-mediated pathway contributes to susceptibility to SLE.

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PETANDA BIOLOGIK TERKINI LUPUS NEFRITIS

INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY ◽

10.24293/ijcpml.v20i2.1085 ◽

2018 ◽

Vol 20 (2) ◽

pp. 154

Author(s):

Hani Susianti ◽

Kusworini Handono

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Gold Standard ◽

Large Scale ◽

Renal Damage ◽

Systemic Lupus ◽

Urine Sediment ◽

Early Relapse ◽

Prognostic Stratification ◽

Novel Biomarkers

Lupus Nephritis (LN) is one of the serious clinical manifestation of Systemic Lupus Erythematosus (SLE). Early detection and treatmentof renal activity may spare patients from renal damage. Conventional biomarkers such as urine sediment, proteinuria, creatinine, antidsDNA antibody and their complement levels are not specific and sensitive enough in detecting the ongoing disease activity in the lupuskidneys and early relapse of nephritis. Renal biopsy is the gold standard in providing information on the histopathology of LN, but isinvasive and it should take a serial of biopsies making it impractical when monitoring LN. Thus, some novel biomarkers are necessary toenhance the diagnostic accuracy and sensitivity of lupus renal disease, prognostic stratification, monitoring of treatment response anddetection of early renal flares as well. Some novel biomarkers have been studied in LN, however, validation on a large scale of patientswith different ethnic backgrounds is still needed.

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Systemic lupus erythematosus: The search for the ideal biomarker

Lupus ◽

10.1177/0961203320979051 ◽

2020 ◽

pp. 096120332097905

Author(s):

Luis Alonso González ◽

Manuel Francisco Ugarte-Gil ◽

Graciela S Alarcón

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Large Scale ◽

Central Nervous System Involvement ◽

Response To Treatment ◽

Systemic Lupus ◽

Cerebrospinal Fluid Biomarkers ◽

Novel Biomarkers ◽

Serological Biomarkers ◽

The Ideal

During the last decades, there has been an increased interest in the discovery and validation of biomarkers that reliably reflect specific aspects of lupus. Although many biomarkers have been developed, few of them have been validated and used in clinical practice, but with unsatisfactory performances. Thus, there is still a need to rigorously validate many of these novel promising biomarkers in large-scale longitudinal studies and also identify better biomarkers not only for lupus diagnosis but also for monitoring and predicting upcoming flares and response to treatment. Besides serological biomarkers, urinary and cerebrospinal fluid biomarkers have emerged for assessing both renal and central nervous system involvement in systemic lupus erythematosus, respectively. Also, novel omics techniques help us to understand the molecular basis of the disease and also allow the identification of novel biomarkers which may be potentially useful for guiding new therapeutic targets.

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Systemic lupus erythematosus after delivery and myasthenia gravis with COL6A1 gene mutation: A case report

European Journal of Inflammation ◽

10.1177/20587392211066424 ◽

2022 ◽

Vol 20 ◽

pp. 205873922110664

Author(s):

Yanqiu Xu ◽

Ying Zhang ◽

Hongming Hu ◽

Jie Tan ◽

Bin Wu

Keyword(s):

Systemic Lupus Erythematosus ◽

Case Report ◽

Autoimmune Diseases ◽

Myasthenia Gravis ◽

Gene Mutation ◽

Lupus Erythematosus ◽

Large Scale ◽

Systemic Lupus ◽

Gene Variation ◽

Pathogenic Genes

The coexistence of systemic lupus erythematosus (SLE) and myasthenia gravis (MG) is rarely reported, especially the appearance of SLE before MG. In addition to the production of autoantibodies after thymectomy, gene mutation may be an important contributing factor to the overlap of SLE and MG. Here, we report a case of a female patient diagnosed with SLE before MG and found to carry the heterozygous variation COL6A1 c. 2608G>A. We propose that this gene variation weakens the function of COL6A1 and indirectly activates STAT1, resulting in the phenotype of these two autoimmune diseases. This report suggests that it is feasible to explore common pathogenic genes in SLE and MG through future large-scale research.

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Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond

Cells ◽

10.3390/cells8101180 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1180 ◽

Cited By ~ 9

Author(s):

Kwon ◽

Chun ◽

Kim ◽

Mak

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Large Scale ◽

Association Studies ◽

Genome Wide Association Studies ◽

Susceptibility Loci ◽

Childbearing Age ◽

Systemic Lupus ◽

Risk Variants ◽

The Impact

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of complex etiology that primarily affects women of childbearing age. The development of SLE is attributed to the breach of immunological tolerance and the interaction between SLE-susceptibility genes and various environmental factors, resulting in the production of pathogenic autoantibodies. Working in concert with the innate and adaptive arms of the immune system, lupus-related autoantibodies mediate immune-complex deposition in various tissues and organs, leading to acute and chronic inflammation and consequent end-organ damage. Over the past two decades or so, the impact of genetic susceptibility on the development of SLE has been well demonstrated in a number of large-scale genetic association studies which have uncovered a large fraction of genetic heritability of SLE by recognizing about a hundred SLE-susceptibility loci. Integration of genetic variant data with various omics data such as transcriptomic and epigenomic data potentially provides a unique opportunity to further understand the roles of SLE risk variants in regulating the molecular phenotypes by various disease-relevant cell types and in shaping the immune systems with high inter-individual variances in disease susceptibility. In this review, the catalogue of SLE susceptibility loci will be updated, and biological signatures implicated by the SLE-risk variants will be critically discussed. It is optimistically hoped that identification of SLE risk variants will enable the prognostic and therapeutic biomarker armamentarium of SLE to be strengthened, a major leap towards precision medicine in the management of the condition.

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Systemic lupus erythematosus on social networking sites: Friends or foes?

Lupus ◽

10.1177/09612033211038053 ◽

2021 ◽

pp. 096120332110380

Author(s):

Alina Dima ◽

Rym Abida ◽

Victoria Sadovici-Bobeica ◽

Caterina Delcea

Keyword(s):

Systemic Lupus Erythematosus ◽

Social Networking ◽

Lupus Erythematosus ◽

Social Networking Sites ◽

Large Scale ◽

Interpersonal Relations ◽

Large Data ◽

Sources Of Information ◽

Systemic Lupus ◽

Potential Benefits

Systemic lupus erythematosus (SLE) is one of the most studied autoimmune diseases. The interest shown for this pathology is translated into international scientific journals, congresses, meetings and, recently, in large data available online. Social networking sites (SNS) have gradually advanced from ways to facilitate interpersonal relations to important sources of information, including medical data regarding SLE, with sites largely accessed by both doctors and patients. Albeit the use of SNS can be valuable in providing education and promoting development of public health, it can be misleading if unprofessional sources of information are used; therefore, both “friends and foes” of the data accessed on large scale should always be considered. This viewpoint is a discussion of the potential benefits and harms related to the SNS use for SLE patients as well as for their physicians.

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Cell-type-specific transcriptome architecture underlying the establishment and exacerbation of systemic lupus erythematosus

10.1101/2022.01.12.22269137 ◽

2022 ◽

Author(s):

Masahiro Nakano ◽

Mineto Ota ◽

Yusuke Takeshima ◽

Yukiko Iwasaki ◽

Hiroaki Hatano ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Large Scale ◽

Immune Cell ◽

Disease State ◽

Cell Type ◽

Sequencing Data ◽

Systemic Lupus ◽

Cell Type Specific

Systemic lupus erythematosus (SLE) is a complex and heterogeneous autoimmune disease involving multiple immune cells. A major hurdle to the elucidation of SLE pathogenesis is our limited understanding of dysregulated gene expression linked to various clinical statuses with a high cellular resolution. Here, we conducted a large-scale transcriptome study with 6,386 RNA sequencing data covering 27 immune cell types from 159 SLE and 89 healthy donors. We first profiled two distinct cell-type-specific transcriptomic signatures: disease-state and disease-activity signatures, reflecting disease establishment and exacerbation, respectively. We next identified candidate biological processes unique to each signature. This study suggested the clinical value of disease-activity signatures, which were associated with organ involvement and responses to therapeutic agents such as belimumab. However, disease-activity signatures were less enriched around SLE risk variants than disease-state signatures, suggesting that the genetic studies to date may not well capture clinically vital biology in SLE. Together, we identified comprehensive gene signatures of SLE, which will provide essential foundations for future genomic, genetic, and clinical studies.

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