Tnfrsf13b variants in systemic lupus erythematosus and primary antibody deficiency

Abstract of poster at the Australasian Society of Clinical Immunology and Allergy (ASCIA) 25th Annual Conference, 10-13 September 2014, Melbourne, Australia

Functional variants of Fc gamma receptor (FCGR2A) and FCGR3A are not associated with susceptibility to systemic sclerosis in a large European study (EUSTAR)

Objective. To investigate the possible role of FCGR2A 519A>G and FCGR3A 559A>C functional polymorphisms in the genetic predisposition to susceptibility to systemic sclerosis (SSc) or clinical phenotype. Methods. A total of 1566 patients with SSc and 2271 geographically matched controls were included in our study. We analyzed the genotype and allele frequencies of the FCGR2A 519A>G and FCGR3A 559A>C functional variants in 6 independent European cohorts of white patients with SSc, and white controls. The cohorts comprised 165 Dutch patients with SSc and 1326 controls, 236 Spanish patients with SSc and 257 controls, 267 German patients with SSc and 270 controls, 202 Swedish patients with SSc and 261 controls, 416 Italian patients with SSc and 157 controls, and additionally 280 English patients with SSc. Genotyping was performed using Taqman 5′ allelic discrimination assay. The study reached a 99% power to detect the effect of a polymorphism at an OR of 1.3. Results. Neither FCGR2A 519A>G nor FCGR3A 559A>C was significantly associated with susceptibility to SSc. We did not find an association with specific disease phenotypes, limited or diffuse cutaneous involvement, autoantibody profiles, or pulmonary involvement. Conclusion. Our study strongly suggests the lack of a role for the FCGR2A 519A>G and FCGR3A 559A>C polymorphisms in SSc susceptibility or clinical phenotype in 6 independent European cohorts. The Journal of Rheumatology Copyright © 2010. All rights reserved

Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus

4 páginas, 2 figuras, 2 tablas.-- Spanish Scleroderma Group.Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22–23, rs2056626, P = 2.09 × 10−7 in the discovery samples, P = 3.39 × 10−9 in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 × 10−18), IRF5 (P = 1.86 × 10−13) and STAT4 (P = 3.37 × 10−9) gene regions as SSc genetic risk factors.This work was supported by the following grants: T.R.D.J.R. was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). J.M. was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucía, Spain and in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain (J.M.). R.B. is supported by the I3P Consejo Superior de Investigaciones Científicas program funded by the 'Fondo Social Europeo'. B.Z.A. is supported by the Netherlands Organization for Health Research and Development (ZonMW grant 016.096.121). B.K. is supported by the Dutch Diabetes Research Foundation (grant 2008.40.001) and the Dutch Arthritis Foundation (Reumafonds, grant NR 09-1-408). Genotyping of the Dutch control samples was sponsored by US National Insitutes of Mental Health funding, R01 MH078075 (R.O.A.). The German controls were from the PopGen biobank (to B.K.).Peer reviewe

Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Funded by EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS (115565), The Spanish Ministry of Economy Industry and Competitiveness (SAF2015-66761-P), The Regional Ministry of Innovation, Science and Technologies of the Andalusian Regional Government (P12-BIO-1395) and Juan de la Cierva fellowship (FJCI-2015-24028). This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences

Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Objective I mmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. Methods We meta-analysed similar to 6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. Results Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. Conclusions We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs