Common Genetic Pathways Implicated RA and SLE

Rheumatoid arthritis and lupus are distinct conditions that present in unique ways, but they do share various genetic risk factors. A recent study revealed a new risk locus for both diseases.

Previously, the genetic overlap between the two hadn’t been thoroughly examined. But, a study published in the May Annals of Rheumatic Diseases identified additional risk loci that are shared between rheumatoid arthritis and lupus.

Using genome-wide association studies, the study, “A combined large-scaled meta-analysis identifies COG6 as a novel shared risk locus for rheumatoid arthritis and systemic lupus erythematosus,” revealed the genetic variant rs9603612 is located near the COG6 (component of oligomeric Golgi complex 6) gene. [[{"type":"media","view_mode":"media_crop","fid":"49060","attributes":{"alt":"©gopixa/Shutterstock.com","class":"media-image media-image-right","id":"media_crop_9654674657770","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5902","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"font-size: 13.008px; line-height: 1.538em; float: right;","title":"©gopixa/Shutterstock.com","typeof":"foaf:Image"}}]]

COG6 is located on chromosome 13q14.11, and it’s crucial to proper protein sorting and glycosylation. However, its role in immune-mediated disorders remains unknown.

This study is the first comprehensive, large-scale analysis that looks into the genetic overlap between both disorders. Small sample sizes has been a limiting factor to-date.

“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,” the authors wrote. “Since common genetic pathways are implicated in rheumatoid arthritis and lupus, a reclassification of patients from a genetic point of view will lead to more specific and effective therapeutic procedures.”

Overall, researchers included 17,552 patients with rheumatoid arthritis, 4,194 patients with lupus, and 46,907 control patients. Data came from Sweden, the United Kingdom, Germany, Italy, Spain, The Netherlands, and the United States.

Through silico expression quantitative trait locus analysis, researchers learned the associated polymorphism acts like a regulator variant that influences COG6 expression. In particular, rs9603612 impacts the transcription factor binding and is linked to gene target expression, most likely regulating COG6 expression in monocytes.   

According to investigators, the protein-protein interaction and gene ontology enrichment analyses pointed to an overlap with specific biological processes. Results pointed specifically to the type I interferon signaling pathway. Additionally, the genetic correlation and polygenic risk score analyses showed cross-phenotype associations between rheumatoid arthritis and lupus.

Bivariate analysis revealed a significant genetic correlation between rheumatoid arthritis and lupus. Polygenic risk score analysis showed significant differences between the case groups and controls and that lupus cases had a significant enrichment of rheumatoid arthritis-risk alleles.

The findings, they said, point to rs9603612 being a good candidate for being the casual variant involved in the genetic predisposition of autoimmune disorders.

References:

Ana Márquez, Laura Vidal-Bralo, et al.

"A combined large-scale meta-analysis identifies

COG6 as a novel shared risk locus for rheumatoid 

arthritis and systemic lupus erythematosus."

Annals of the Rheumatic Diseases.

ARD Online First, published on May 18, 2016 as 10.1136/annrheumdis-2016-209436