Background/Purpose: One of the main limitations of the association studies in autoimmunity is the difficulty in identifying genetic risk variants with modest effects, given the large sample size required and the relatively low prevalence of these diseases in the general population. This limitation has been partially overcome by combining GWAS data from different pathologies as a single phenotype, thus providing the statistical power lacking in GWAS datasets of a specific disease. This approach has already been successfully applied in the study of several autoimmune diseases with common genetic backgrounds. During the last years, genome-wide association studies (GWAS) 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 thus far. The aim of the present study was therefore to identify novel shared risk loci between RA and SLE by performing a combined meta-analysis including previously published GWAS datasets of both diseases.

Methods: We performed a large-scale meta-analysis of GWAS data from RA (3,911 cases and 4,083 controls) and SLE (2,237 cases and 6,315 controls). Statistical analyses were performed with PLINK V.1.07. First, disease-specific meta-analyses were performed combining RA datasets, on one hand, and SLE datasets, on the other hand, by an inverse variance-weighted method. Subsequently, a combined RA–SLE meta-analysis was conducted. Those SNPs with p values lower than 1×10⁻⁵ in this combined meta-GWAS and p values lower than 0.01 in each disease meta-analysis were selected for replication in additional datasets comprising 13,641 RA cases and 31,921 controls and 1,957 SLE patients and 4,588 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 in monocytes. 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.

Conclusion:  In summary, the present study adds COG6 to the list of risk factors shared between RA and SLE. Our results highlight the existence of a relevant genetic correlation between both diseases as well as the influence of common molecular mechanisms in their pathophysiology. Since common genetic pathways are implicated in RA and SLE, a reclassification of patients from a genetic point of view will lead to more specific and effective therapeutic procedures.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-combined-large-scale-meta-analysis-identifies-cog6-as-a-novel-shared-risk-locus-for-rheumatoid-arthritis-and-systemic-lupus-erythematosus/