Objectives During 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.
Methods We 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.
Results The 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.
Conclusions In 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.
- Rheumatoid Arthritis
- Systemic Lupus Erythematosus
- Gene Polymorphism
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Handling editor Tore K Kvien
Contributors AM and JM were involved in the conception and design of the study and contributed in the analysis and interpretation of data. AM drafted the manuscript. LV-B, LR-R, MAG-G, AB, IG-A, PC, NO-C, MMA-G, FJG-H, MFG-E, JMS, CT, AS, AG, LP, JW, TV and MEA-R collected samples and participated in analysis and interpretation of data. LV-B, LR-R, MAG-G, AB, IG-A, PC, NO-C, MMA-G, FJG-H, MFG-E, JMS, CT, AS, AG, LP, JW, TV, MEA-R and JM revised critically the manuscript draft. All authors approved the final version of the manuscript.
Funding This work was supported by the following grants: SAF2012-34435 from the Spanish Ministry of Economy and Competitiveness, P12-BIO-1395 from Consejería de Innovación, Ciencia y Tecnología, Junta de Andalucía (Spain), the European IMI BTCure Program, the EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS (ref: 115565), the Cooperative Research Thematic Network (RETICS) programme, RD12/0009/0004 (RIER), from Instituto de Salud Carlos III (ISCIII, Health Ministry, Madrid, Spain) and PI12/02558 from Instituto de Salud Carlos III (ISCIII, Health Ministry, Madrid, Spain). AM is recipient of a Rio Hortega fellowship (CM13/00314) from the Ministry of Economy and Competitiveness through the Instituto de Salud Carlos III (ISCIII, Health Ministry, Madrid, Spain).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Comité de Bioética del Consejo Superior de Investigaciones Científicas and the local ethical committees of the different participating centres.
Provenance and peer review Not commissioned; externally peer reviewed.