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

2010 ◽  
Vol 2010 ◽  
pp. 1-5 ◽  
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.

scholarly journals Association of NCF1 polymorphism with systemic lupus erythematosus and systemic sclerosis but not with ANCA-associated vasculitis in a Japanese population

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nozomi Yokoyama ◽  
Aya Kawasaki ◽  
Takashi Matsushita ◽  
Hiroshi Furukawa ◽  
Yuya Kondo ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Systemic Sclerosis ◽  
Lupus Erythematosus ◽  
Japanese Population ◽  
Association Studies ◽  
Conditional Logistic Regression ◽  
Strong Association ◽  
Genome Wide Association Studies ◽  
Systemic Lupus ◽  
Anca Associated Vasculitis

Abstract Genome-wide association studies of systemic lupus erythematosus (SLE) in Chinese and Korean populations demonstrated strong association of single nucleotide polymorphisms (SNPs) located in the GTF2I-NCF1 region, rs73366469 (GTF2I), rs117026326 (GTF2I), rs80346167(GTF2IRD1) and rs201802880 (NCF1). This region has also been associated with susceptibility to Sjögren syndrome and rheumatoid arthritis; however, association studies with systemic sclerosis (SSc) and ANCA-associated vasculitis (AAV) have not been reported. Here we made an attempt to confirm their associations with SLE in the Japanese population, to find the primarily associated SNP, and to investigate whether these SNPs are also associated with susceptibility to SSc and AAV. By genotyping these four SNPs on 842 SLE, 467 SSc, 477 AAV patients and 934 healthy controls, striking association was confirmed in Japanese SLE. In addition, these SNPs were significantly associated with susceptibility to SSc, but not with AAV. Conditional logistic regression analysis revealed that the association of NCF1 rs201802880, a missense SNP encoding p.Arg90His, can account for the association of other SNPs by linkage disequilibrium. These results suggested that GTF2I-NCF1 region is associated with susceptibility to multiple autoimmune rheumatic diseases but not with AAV, and the primarily associated variant may be the missense SNP in NCF1.

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

2020 ◽  
Vol 9 (3) ◽  
pp. 712 ◽  
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.

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

2018 ◽  
Vol 77 (7) ◽  
pp. 1078-1084 ◽  
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.

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

2012 ◽  
Vol 2012 ◽  
pp. 1-17 ◽  
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.

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

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
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.

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

2012 ◽  
Vol 71 (5) ◽  
pp. 777-784 ◽  
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.

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

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.

scholarly journals Genetic Variation in C-Reactive Protein (CRP) Gene May Be Associated with Risk of Systemic Lupus Erythematosus and CRP Concentrations

2008 ◽  
Vol 35 (11) ◽  
pp. 2171-2178 ◽  
Author(s):  
P. BETTY SHIH ◽  
SUSAN MANZI ◽  
PENNY SHAW ◽  
MARGARET KENNEY ◽  
AMY H. KAO ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Association Studies ◽  
Susceptibility Gene ◽  
C Reactive Protein ◽  
Systemic Lupus ◽  
Unique Haplotype ◽  
Reactive Protein ◽  
Independent Population ◽  
Serum Crp

ObjectiveThe gene coding for C-reactive protein (CRP) is located on chromosome 1q23.2, which falls within a linkage region thought to harbor a systemic lupus erythematosus (SLE) susceptibility gene. Recently, 2 single-nucleotide polymorphisms (SNP) in the CRP gene (+838, +2043) have been shown to be associated with CRP concentrations and/or SLE risk in a British family-based cohort. Our study was done to confirm the reported association in an independent population-based case-control cohort, and also to investigate the influence of 3 additional CRP tagSNP (−861, −390, +90) on SLE risk and serum CRP concentrations.MethodsDNA from 337 Caucasian women who met the American College of Rheumatology criteria for definite (n = 324) or probable (n = 13) SLE and 448 Caucasian healthy female controls was genotyped for 5 CRP tagSNP (−861, −390, +90, +838, +2043). Genotyping was performed using restriction fragment length polymorphism-polymerase chain reaction, pyrosequencing, or TaqMan assays. Serum CRP levels were measured using ELISA. Association studies were performed using the chi-squared distribution, Z-test, Fisher’s exact test, and analysis of variance. Haplotype analysis was performed using EH software and the haplo.stats package in R 2.1.2.ResultsWhile none of the SNP were found to be associated with SLE risk individually, there was an association with the 5 SNP haplotypes (p < 0.001). Three SNP (−861, −390, +90) were found to significantly influence serum CRP level in SLE cases, both independently and as haplotypes.ConclusionOur data suggest that unique haplotype combinations in the CRP gene may modify the risk of developing SLE and influence circulating CRP levels.

scholarly journals Independent Replication and Metaanalysis of Association Studies Establish TNFSF4 as a Susceptibility Gene Preferentially Associated with the Subset of Anticentromere-positive Patients with Systemic Sclerosis

2012 ◽  
Vol 39 (5) ◽  
pp. 997-1003 ◽  
Author(s):  
BAPTISTE COUSTET ◽  
MATTHIEU BOUAZIZ ◽  
PHILIPPE DIEUDÉ ◽  
MICKAEL GUEDJ ◽  
LARA BOSSINI-CASTILLO ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Lupus Erythematosus ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Causal Variant ◽  
Allelic Association ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Independent Replication ◽  
Preferential Association

Objective.Independent replication with large cohorts and metaanalysis of genetic associations are necessary to validate genetic susceptibility factors. The known tumor necrosis factor (ligand) superfamily, member 4 gene (TNFSF4) systemic lupus erythematosus (SLE) risk locus has been found to be associated with systemic sclerosis (SSc) in 2 studies, but with discrepancies between them for genotype-phenotype correlation. Our objective was to validate TNFSF4 association with SSc and determine the subset with the higher risk.Methods.Known SLE and SSc TNFSF4 susceptibility variants (rs2205960, rs1234317, rs12039904, rs10912580, and rs844648) were genotyped in 1031 patients with SSc and 1014 controls of French white ancestry. Genotype-phenotype association analysis and metaanalysis of available data were performed, providing a population study of 4989 patients with SSc and 4661 controls, all of European white ancestry.Results.Allelic and genotypic associations were observed for the 5 single-nucleotide polymorphisms (SNP) with the subset of patients with SSc who are positive for anticentromere antibodies (ACA) and only a trend for association with SSc and limited cutaneous SSc. Rs2205960 exhibited the strongest allelic association in ACA+ patients with SSc [p = 0.0015; OR 1.37 (1.12–1.66)], with significant intra-cohort association when compared to patients with SSc positive for ACA. Metaanalysis confirmed overall association with SSc but also raised preferential association with the ACA+ subset and strongest effect with rs2205960 [T allele p = 0.00013; OR 1.33 (1.15–1.54) and TT genotype p = 0.00046; OR 2.02 (1.36–2.98)].Conclusion.We confirm TNFSF4 as an SSc susceptibility gene and rs2205960 as a putative causal variant with preferential association in the ACA+ SSc subphenotype.

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