scholarly journals A combined large-scale meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus

2016 ◽  
Vol 76 (1) ◽  
pp. 286-294 ◽  
Author(s):  
Ana Márquez ◽  
Laura Vidal-Bralo ◽  
Luis Rodríguez-Rodríguez ◽  
Miguel A González-Gay ◽  
Alejandro Balsa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Large Scale ◽  
Meta Analysis ◽  
Polygenic Risk Score ◽  
Type I ◽  
Systemic Lupus ◽  
Genome Wide ◽  
Genetic Overlap

ObjectivesDuring the last years, genome-wide association studies (GWASs) have identified a number of common genetic risk factors for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, the genetic overlap between these two immune-mediated diseases has not been thoroughly examined so far. The aim of the present study was to identify additional risk loci shared between RA and SLE.MethodsWe performed a large-scale meta-analysis of GWAS data from RA (3911 cases and 4083 controls) and SLE (2237 cases and 6315 controls). The top-associated polymorphisms in the discovery phase were selected for replication in additional datasets comprising 13 641 RA cases and 31 921 controls and 1957 patients with SLE and 4588 controls.ResultsThe rs9603612 genetic variant, located nearby the COG6 gene, an established susceptibility locus for RA, reached genome-wide significance in the combined analysis including both discovery and replication sets (p value=2.95E−13). In silico expression quantitative trait locus analysis revealed that the associated polymorphism acts as a regulatory variant influencing COG6 expression. Moreover, protein–protein interaction and gene ontology enrichment analyses suggested the existence of overlap with specific biological processes, specially the type I interferon signalling pathway. Finally, genetic correlation and polygenic risk score analyses showed cross-phenotype associations between RA and SLE.ConclusionsIn conclusion, we have identified a new risk locus shared between RA and SLE through a meta-analysis including GWAS datasets of both diseases. This study represents the first comprehensive large-scale analysis on the genetic overlap between these two complex disorders.

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

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.

scholarly journals Study of the common genetic background for rheumatoid arthritis and systemic lupus erythematosus

2010 ◽  
Vol 70 (3) ◽  
pp. 463-468 ◽  
Author(s):  
Gisela Orozco ◽  
Steve Eyre ◽  
Anne Hinks ◽  
John Bowes ◽  
Ann W Morgan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Meta Analysis ◽  
Trend Test ◽  
Nucleotide Polymorphisms ◽  
Systemic Lupus ◽  
Genotype Frequencies ◽  
Genome Wide ◽  
Significance Levels

BackgroundEvidence is beginning to emerge that there may be susceptibility loci for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) that are common to both diseases.ObjectiveTo investigate single nucleotide polymorphisms that have been reported to be associated with SLE in a UK cohort of patients with RA and controls.Methods3962 patients with RA and 9275 controls were included in the study. Eleven SNPs mapping to confirmed SLE loci were investigated. These mapped to the TNFSF4, BANK1, TNIP1, PTTG1, UHRF1BP1, ATG5, JAZF1, BLK, KIAA1542, ITGAM and UBE2L3 loci. Genotype frequencies were compared between patients with RA and controls using the trend test.ResultsThe SNPs mapping to the BLK and UBE2L3 loci showed significant evidence for association with RA. Two other SNPs, mapping to ATG5 and KIAA1542, showed nominal evidence for association with RA (p=0.02 and p=0.02, respectively) but these were not significant after applying a Bonferroni correction. Additionally, a significant global enrichment in carriage of SLE alleles in patients with RA compared with controls (p=9.1×10−7) was found. Meta-analysis of this and previous studies confirmed the association of the BLK and UBE2L3 gene with RA at genome-wide significance levels (p<5×10−8). Together, the authors estimate that the SLE and RA overlapping loci, excluding HLA-DRB1 alleles, identified so far explain ∼5.8% of the genetic susceptibility to RA as a whole.ConclusionThe findings confirm the association of the BLK and UBE2L3 loci with RA, thus adding to the list of loci showing overlap between RA and SLE.

Associations between Polymorphisms in the IL-1 Gene and the Risk of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Evidence from a Meta-Analysis

2020 ◽  
pp. 1-9
Author(s):  
Lin Zhu ◽  
Peng Chen ◽  
Xuanjing Sun ◽  
Shuo Zhang
Keyword(s):  
Rheumatoid Arthritis ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Web Of Science ◽  
Meta Analysis ◽  
Interleukin 1 ◽  
Systemic Lupus

<b><i>Background:</i></b> Previous studies on polymorphisms in interleukin-1 (<i>IL-1</i>) and the risk of rheumatoid arthritis (RA)/systemic lupus erythematosus (SLE) yielded inconsistent results. <b><i>Objectives:</i></b> The authors performed this meta-analysis to more robustly evaluate associations between polymorphisms in the <i>IL-1</i> gene and the risk of RA/SLE. <b><i>Methods:</i></b> MEDLINE, Embase, Web of Science, Wanfang, VIP, and CNKI were systematically searched for eligible studies, and 34 relevant studies were finally selected to be eligible for inclusion. <b><i>Results:</i></b> We found that <i>IL-1A</i> +4845G/T polymorphism was significantly associated with the risk of RA in the overall population (dominant comparison: <i>p</i> = 0.02; overdominant comparison: <i>p</i> = 0.05; allele comparison: <i>p</i> = 0.04), whereas <i>IL-1B</i> +3954C/T polymorphism was significantly associated with the risk of RA in the overall population (overdominant comparison: <i>p</i> = 0.03; allele comparison: <i>p</i> = 0.01) and Asians (recessive comparison: <i>p</i> = 0.007; allele comparison: <i>p</i> = 0.002). In addition, we found that <i>IL-1A</i> –889C/T polymorphism was significantly associated with the risk of SLE in Caucasians (allele comparison: <i>p</i> = 0.04), <i>IL-1B</i> –31T/C polymorphism was significantly associated with the risk of SLE in the overall population (recessive comparison: <i>p</i> = 0.04), and <i>IL-1B</i> –511C/T polymorphism was significantly associated with the risk of SLE in Asians (recessive comparison: <i>p</i> = 0.01; allele comparison: <i>p</i> = 0.03). <b><i>Conclusions:</i></b> This meta-analysis suggests that <i>IL-1A</i> +4845G/T and <i>IL-1B</i> +3954C/T polymorphisms may influence the risk of RA, whereas <i>IL-1A</i> –889C/T, <i>IL-1B</i> –31T/C, and <i>IL-1B</i> –511C/T polymorphisms may influence the risk of SLE.

scholarly journals Meta-analysis of genome-wide linkage studies of systemic lupus erythematosus

2006 ◽  
Vol 7 (7) ◽  
pp. 609-614 ◽  
Author(s):  
P Forabosco ◽  
J D Gorman ◽  
C Cleveland ◽  
J A Kelly ◽  
S A Fisher ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Meta Analysis ◽  
Linkage Studies ◽  
Systemic Lupus ◽  
Genome Wide

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

2012 ◽  
Vol 71 (11) ◽  
pp. 1809-1814 ◽  
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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