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

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.

Download Full-text

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.

Download Full-text

Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-219209 ◽

2020 ◽

pp. annrheumdis-2020-219209

Author(s):

Xianyong Yin ◽

Kwangwoo Kim ◽

Hiroyuki Suetsugu ◽

So-Young Bang ◽

Leilei Wen ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Large Scale ◽

Meta Analysis ◽

Genetic Correlations ◽

Susceptibility Loci ◽

Systemic Lupus ◽

East Asians ◽

Genome Wide ◽

Causal Variants

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.

Download Full-text

Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-213093 ◽

2018 ◽

Vol 77 (7) ◽

pp. 1078-1084 ◽

Cited By ~ 10

Author(s):

Yong-Fei Wang ◽

Yan Zhang ◽

Zhengwei Zhu ◽

Ting-You Wang ◽

David L Morris ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Fine Mapping ◽

Lupus Erythematosus ◽

Drug Repositioning ◽

Association Studies ◽

Genome Wide Association Studies ◽

Systemic Lupus ◽

Genome Wide ◽

Causal Variants

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.

Download Full-text

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.

Download Full-text

Genome-wide pathway analysis of genome-wide association studies on systemic lupus erythematosus and rheumatoid arthritis

Molecular Biology Reports ◽

10.1007/s11033-012-1952-x ◽

2012 ◽

Vol 39 (12) ◽

pp. 10627-10635 ◽

Cited By ~ 64

Author(s):

Young Ho Lee ◽

Sang-Cheol Bae ◽

Sung Jae Choi ◽

Jong Dae Ji ◽

Gwan Gyu Song

Keyword(s):

Rheumatoid Arthritis ◽

Systemic Lupus Erythematosus ◽

Pathway Analysis ◽

Lupus Erythematosus ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Systemic Lupus ◽

Genome Wide

Download Full-text

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.

Download Full-text

Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5, HLA-DPB1 and HLA-G

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2011-200808 ◽

2012 ◽

Vol 71 (5) ◽

pp. 777-784 ◽

Cited By ~ 48

Author(s):

Michelle M A Fernando ◽

Jan Freudenberg ◽

Annette Lee ◽

David Lester Morris ◽

Lora Boteva ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Association Studies ◽

Organ Damage ◽

Genome Wide Association Studies ◽

Systemic Lupus ◽

Chinese Populations ◽

Risk Alleles ◽

Snp Mapping ◽

Hla Dqa1

ObjectivesSystemic lupus erythematosus (SLE) is a chronic multisystem genetically complex autoimmune disease characterised by the production of autoantibodies to nuclear and cellular antigens, tissue inflammation and organ damage. Genome-wide association studies have shown that variants within the major histocompatibility complex (MHC) region on chromosome 6 confer the greatest genetic risk for SLE in European and Chinese populations. However, the causal variants remain elusive due to tight linkage disequilibrium across disease-associated MHC haplotypes, the highly polymorphic nature of many MHC genes and the heterogeneity of the SLE phenotype.MethodsA high-density case-control single nucleotide polymorphism (SNP) study of the MHC region was undertaken in SLE cohorts of Spanish and Filipino ancestry using a custom Illumina chip in order to fine-map association signals in these haplotypically diverse populations. In addition, comparative analyses were performed between these two datasets and a northern European UK SLE cohort. A total of 1433 cases and 1458 matched controls were examined.ResultsUsing this transancestral SNP mapping approach, novel independent loci were identified within the MHC region in UK, Spanish and Filipino patients with SLE with some evidence of interaction. These loci include HLA-DPB1, HLA-G and MSH5 which are independent of each other and HLA-DRB1 alleles. Furthermore, the established SLE-associated HLA-DRB1*15 signal was refined to an interval encompassing HLA-DRB1 and HLA-DQA1. Increased frequencies of MHC region risk alleles and haplotypes were found in the Filipino population compared with Europeans, suggesting that the greater disease burden in non-European SLE may be due in part to this phenomenon.ConclusionThese data highlight the usefulness of mapping disease susceptibility loci using a transancestral approach, particularly in a region as complex as the MHC, and offer a springboard for further fine-mapping, resequencing and transcriptomic analysis.

Download Full-text

Association ofTNFAIP3Polymorphism with Susceptibility to Systemic Lupus Erythematosus in a Japanese Population

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/207578 ◽

2010 ◽

Vol 2010 ◽

pp. 1-5 ◽

Cited By ~ 25

Author(s):

Aya Kawasaki ◽

Ikue Ito ◽

Satoshi Ito ◽

Taichi Hayashi ◽

Daisuke Goto ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Japanese Population ◽

Association Studies ◽

Susceptibility Gene ◽

Allelic Association ◽

Genome Wide Association Studies ◽

Mrna Levels ◽

Nucleotide Polymorphisms ◽

Systemic Lupus

Recent genome-wide association studies demonstrated association of single nucleotide polymorphisms (SNPs) in theTNFAIP3region at 6q23 with systemic lupus erythematosus (SLE) in European-American populations. In this study, we investigated whether SNPs in theTNFAIP3region are associated with SLE also in a Japanese population. A case-control association study was performed on the SNPs rs13192841, rs2230926, and rs6922466 in 318 Japanese SLE patients and 444 healthy controls. Association of rs2230926 G allele with SLE was replicated in Japanese (allelic associationP=.033, odds ratio [OR] 1.47, recessive modelP=.023, OR 8.52). The association was preferentially observed in the SLE patients with nephritis. When theTNFAIP3mRNA levels of the HapMap samples were examined using GENEVAR database, the presence ofTNFAIP3rs2230926 G allele was associated with lower mRNA expression ofTNFAIP3(P=.013). These results indicated thatTNFAIP3is a susceptibility gene to SLE both in the Caucasian and Asian populations.

Download Full-text

Detection of Genetic Overlap Between Rheumatoid Arthritis and Systemic Lupus Erythematosus Using GWAS Summary Statistics

Frontiers in Genetics ◽

10.3389/fgene.2021.656545 ◽

2021 ◽

Vol 12 ◽

Author(s):

Haojie Lu ◽

Jinhui Zhang ◽

Zhou Jiang ◽

Meng Zhang ◽

Ting Wang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Systemic Lupus Erythematosus ◽

Genetic Correlation ◽

Lupus Erythematosus ◽

Association Studies ◽

Integrative Analysis ◽

Genome Wide Association Studies ◽

Summary Statistics ◽

Systemic Lupus ◽

Genetic Components

BackgroundClinical and epidemiological studies have suggested systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are comorbidities and common genetic etiologies can partly explain such coexistence. However, shared genetic determinations underlying the two diseases remain largely unknown.MethodsOur analysis relied on summary statistics available from genome-wide association studies of SLE (N = 23,210) and RA (N = 58,284). We first evaluated the genetic correlation between RA and SLE through the linkage disequilibrium score regression (LDSC). Then, we performed a multiple-tissue eQTL (expression quantitative trait loci) weighted integrative analysis for each of the two diseases and aggregated association evidence across these tissues via the recently proposed harmonic mean P-value (HMP) combination strategy, which can produce a single well-calibrated P-value for correlated test statistics. Afterwards, we conducted the pleiotropy-informed association using conjunction conditional FDR (ccFDR) to identify potential pleiotropic genes associated with both RA and SLE.ResultsWe found there existed a significant positive genetic correlation (rg = 0.404, P = 6.01E-10) via LDSC between RA and SLE. Based on the multiple-tissue eQTL weighted integrative analysis and the HMP combination across various tissues, we discovered 14 potential pleiotropic genes by ccFDR, among which four were likely newly novel genes (i.e., INPP5B, OR5K2, RP11-2C24.5, and CTD-3105H18.4). The SNP effect sizes of these pleiotropic genes were typically positively dependent, with an average correlation of 0.579. Functionally, these genes were implicated in multiple auto-immune relevant pathways such as inositol phosphate metabolic process, membrane and glucagon signaling pathway.ConclusionThis study reveals common genetic components between RA and SLE and provides candidate associated loci for understanding of molecular mechanism underlying the comorbidity of the two diseases.

Download Full-text