Several Critical Cell Types, Tissues, and Pathways Are Implicated in Genome-Wide Association Studies for Systemic Lupus Erythematosus

ObjectivesSystemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning.MethodsWe conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning.ResultsWe identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, pmeta=4.40E-08), MFHAS1 (rs2428, pmeta=1.17E-08) and CSNK2A2 (rs2731783, pmeta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, pmeta=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in B-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (OR=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE.ConclusionThis study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.

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Role of Cytokines in Systemic Lupus Erythematosus: Recent Progress from GWAS and Sequencing

Journal of Biomedicine and Biotechnology ◽

10.1155/2012/798924 ◽

2012 ◽

Vol 2012 ◽

pp. 1-17 ◽

Cited By ~ 15

Author(s):

John J. Connolly ◽

Hakon Hakonarson

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Association Studies ◽

Monozygotic Twins ◽

Autoimmune Disorder ◽

Genome Wide Association Studies ◽

Systemic Lupus ◽

Genome Wide ◽

Number Variation

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, known to have a strong genetic component. Concordance between monozygotic twins is approximately 30–40%, which is 8–20 times higher than that of dizygotic twins. In the last decade, genome-wide approaches to understanding SLE have yielded many candidate genes, which are important to understanding the pathophysiology of the disease and potential targets for pharmaceutical intervention. In this paper, we focus on the role of cytokines and examine how genome-wide association studies, copy number variation studies, and next-generation sequencing are being employed to understand the etiology of SLE. Prominent genes identified by these approaches includeBLK, FCγR3B,andTREX1. Our goal is to present a brief overview of genomic approaches to SLE and to introduce some of the key discussion points pertinent to the field.

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Role of MHC-Linked Susceptibility Genes in the Pathogenesis of Human and Murine Lupus

Clinical and Developmental Immunology ◽

10.1155/2012/584374 ◽

2012 ◽

Vol 2012 ◽

pp. 1-15 ◽

Cited By ~ 17

Author(s):

Manfred Relle ◽

Andreas Schwarting

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Association Studies ◽

Susceptibility Genes ◽

Genome Wide Association Studies ◽

Systemic Lupus ◽

Nuclear Antigens ◽

Genome Wide ◽

Conventional Drug

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies against nuclear antigens and a systemic inflammation that can damage a broad spectrum of organs. SLE patients suffer from a wide variety of symptoms, which can affect virtually almost any tissue. As lupus is difficult to diagnose, the worldwide prevalence of SLE can only be roughly estimated to range from 10 and 200 cases per 100,000 individuals with dramatic differences depending on gender, ethnicity, and location. Although the treatment of this disease has been significantly ameliorated by new therapies, improved conventional drug therapy options, and a trained expert eye, the underlying pathogenesis of lupus still remain widely unknown. The complex etiology reflects the complex genetic background of the disease, which is also not well understood yet. However, in the past few years advances in lupus genetics have been made, notably with the publication of genome-wide association studies (GWAS) in humans and the identification of susceptibility genes and loci in mice. This paper reviews the role of MHC-linked susceptibility genes in the pathogenesis of systemic lupus erythematosus.

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Genome-Wide Association Study in African-Americans with Systemic Lupus Erythematosus

10.21236/ada592038 ◽

2013 ◽

Author(s):

John Harley

Keyword(s):

Systemic Lupus Erythematosus ◽

African Americans ◽

Association Study ◽

Lupus Erythematosus ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Systemic Lupus ◽

Genome Wide

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New Horizons in the Genetic Etiology of Systemic Lupus Erythematosus and Lupus-Like Disease: Monogenic Lupus and Beyond

Journal of Clinical Medicine ◽

10.3390/jcm9030712 ◽

2020 ◽

Vol 9 (3) ◽

pp. 712 ◽

Cited By ~ 4

Author(s):

Erkan Demirkaya ◽

Sezgin Sahin ◽

Micol Romano ◽

Qing Zhou ◽

Ivona Aksentijevich

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Current Knowledge ◽

Association Studies ◽

Severe Disease ◽

Genetic Diagnosis ◽

Genome Wide Association Studies ◽

Systemic Lupus ◽

Degree Relative ◽

Adult Age

Systemic lupus erythematosus (SLE) is a clinically and genetically heterogeneous autoimmune disease. The etiology of lupus and the contribution of genetic, environmental, infectious and hormonal factors to this phenotype have yet to be elucidated. The most straightforward approach to unravel the molecular pathogenesis of lupus may rely on studies of patients who present with early-onset severe phenotypes. Typically, they have at least one of the following clinical features: childhood onset of severe disease (<5 years), parental consanguinity, and presence of family history for autoimmune diseases in a first-degree relative. These patients account for a small proportion of patients with lupus but they inform considerable knowledge about cellular pathways contributing to this inflammatory phenotype. In recent years with the aid of new sequencing technologies, novel or rare pathogenic variants have been reported in over 30 genes predisposing to SLE and SLE-like diseases. Future studies will likely discover many more genes with private variants associated to lupus-like phenotypes. In addition, genome-wide association studies (GWAS) have identified a number of common alleles (SNPs), which increase the risk of developing lupus in adult age. Discovery of a possible shared immune pathway in SLE patients, either with rare or common variants, can provide important clues to better understand this complex disorder, it’s prognosis and can help guide new therapeutic approaches. The aim of this review is to summarize the current knowledge of the clinical presentation, genetic diagnosis and mechanisms of disease in patents with lupus and lupus-related phenotypes.

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