scholarly journals Genome-wide assessment of genetic risk for systemic lupus erythematosus and disease severity

2019 ◽  
Author(s):  
Lingyan Chen ◽  
Yong-Fei Wang ◽  
Lu Liu ◽  
Adrianna Bielowka ◽  
Rahell Ahmed ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Renal Disease ◽  
Disease Severity ◽  
Lupus Erythematosus ◽  
Genetic Risk ◽  
Age Of Onset ◽  
Genome Wide Association Studies ◽  
Systemic Lupus ◽  
Chinese Populations ◽  
Genome Wide

AbstractObjectiveUsing three European and two Chinese genome-wide association studies (GWAS), we investigated the performance of genetic risk scores (GRS) for predicting the susceptibility and severity of Systemic lupus erythematosus (SLE), using renal disease as a proxy for severity.MethodsWe used four GWASs to test the performance of GRS both cross validating within the European population and between European and Chinese populations. The performance of GRS in SLE risk prediction was evaluated by Receiver Operating Characteristic (ROC) curves. We then analyzed the polygenic nature of SLE statistically. We also partitioned patients according to their age-of-onset and evaluated the predictability of GRS in disease severity in each age group.ResultsWe found consistently that the best GRS in the prediction of SLE used SNPs associated at the level of P<1e-05 in all GWAS datasets and that SNPs with P-values above 0.2 were inflated for SLE true positive signals. The GRS results in an area under the ROC curve ranging between 0.64 and 0.72, within European and between the European and Chinese populations. We further showed a significant positive correlation between a GRS and renal disease in two independent European GWAS (Pcohort1=2.44e-08; Pcohort2=0.00205) and a significant negative correlation with age of SLE onset (Pcohort1=1.76e-12; Pcohort2=0.00384). We found that the GRS performed better in prediction of renal disease in the ‘later onset’ compared to the ‘earlier onset’ group.ConclusionThe GRS predicts SLE in both European and Chinese populations and correlates with poorer prognostic factors: young age of onset and lupus nephritis.

scholarly journals Genome-wide assessment of genetic risk for systemic lupus erythematosus and disease severity

2020 ◽  
Vol 29 (10) ◽  
pp. 1745-1756 ◽  
Author(s):  
Lingyan Chen ◽  
Yong-Fei Wang ◽  
Lu Liu ◽  
Adrianna Bielowka ◽  
Rahell Ahmed ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Renal Disease ◽  
Disease Severity ◽  
Lupus Erythematosus ◽  
Genetic Risk ◽  
Age Of Onset ◽  
Genome Wide Association Studies ◽  
Systemic Lupus ◽  
Chinese Populations ◽  
Genome Wide

Abstract Using three European and two Chinese genome-wide association studies (GWAS), we investigated the performance of genetic risk scores (GRSs) for predicting the susceptibility and severity of systemic lupus erythematosus (SLE), using renal disease as a proxy for severity. We used four GWASs to test the performance of GRS both cross validating within the European population and between European and Chinese populations. The performance of GRS in SLE risk prediction was evaluated by receiver operating characteristic (ROC) curves. We then analyzed the polygenic nature of SLE statistically. We also partitioned patients according to their age-of-onset and evaluated the predictability of GRS in disease severity in each age group. We found consistently that the best GRS in the prediction of SLE used SNPs associated at the level of P &lt; 1e−05 in all GWAS data sets and that SNPs with P-values above 0.2 were inflated for SLE true positive signals. The GRS results in an area under the ROC curve ranging between 0.64 and 0.72, within European and between the European and Chinese populations. We further showed a significant positive correlation between a GRS and renal disease in two independent European GWAS (Pcohort1 = 2.44e−08; Pcohort2 = 0.00205) and a significant negative correlation with age of SLE onset (Pcohort1 = 1.76e−12; Pcohort2 = 0.00384). We found that the GRS performed better in the prediction of renal disease in the ‘later onset’ compared with the ‘earlier onset’ group. The GRS predicts SLE in both European and Chinese populations and correlates with poorer prognostic factors: young age-of-onset and lupus nephritis.

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.

SYSTEMIC LUPUS ERYTHEMATOSUS IN CHILDHOOD

PEDIATRICS ◽  
1968 ◽  
Vol 42 (1) ◽  
pp. 37-49
Author(s):  
Aaron G. Meislin ◽  
Naomi Rothfield
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Renal Disease ◽  
Lupus Erythematosus ◽  
Age Of Onset ◽  
Renal Involvement ◽  
Survival Models ◽  
High Dose ◽  
Systemic Lupus ◽  
Similar Frequency ◽  
Similar Survival

Data on 42 children with systemic lupus erythematosus have been analyzed and compared with data from 200 adults with the disease. Among the children, the age of onset ranged from 3 to 15 years of age, with a peak for girls during adolescence. The age of onset among male patients, both adult and children, was constant for all decades and there was no cluster at any particular age. The disease in children was similar to that in adults except for a higher incidence of hepatosplenomegaly and lymphadenopathy among the children. Renal disease occurred with similar frequency in the two groups. It was generally unusual for additional system involvement to occur following diagnosis, although some patients who had no renal disease at the time of diagnosis did develop renal disease subsequently. Combined antimalarial and moderately high dose steroid therapy was employed. Renal involvement at the time of diagnosis reduced survival among both the adults and the children. The prognosis in childhood was decidedly worse than in adults. Models of survival were developed based upon crude mortality rates. Similar survival models may serve to study prognosis of other diseases and other management of lupus.

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