A previously unknown locus for rheumatoid arthritis (RA) susceptibility has been identified by researchers from the United Kingdom involved in the genome-wide association studies (GWAS), according to a recent study (Orozco G, et al. Arthritis Rheum. 2014;66:24-30). The new locus (rs1043099), located on chromosome 22q12 was found in an expanded cohort of UK patients; 32 RA loci have already been identified. These 30-plus gene regions account for <50% of the total genetic heritability of RA, said the investigators, but may eventually lead to therapeutic approaches.
“Increasing the number of known disease loci will facilitate the estimation of disease risk, potentially allow early intervention in high-risk groups, possibly informing prognosis, and, ultimately, aiding in the discovery of novel targets for pharmacologic therapy,” wrote senior investigator Stephen Eyre, PhD, Senior Research Fellow, Arthritis Research UK Epidemiology Unit, University of Manchester, United Kingdom, and colleagues.
The expanded UK cohort of RA cases and controls added 1361 patients with RA and 2334 healthy controls to the existing UK GWAS base; in all, 3034 patients with RA and 5271 healthy controls were available for analysis. The additional cases and controls expand the power to identify novel RA risk loci in this UK population, the investigators stated.
The genotype data for RA cases and association testing of more than 1.8 million single-nucleotide polymorphisms (SNPs) were evaluated.
The results of the bioinformatics analyses showed that 6 novel RA loci previously associated with other autoimmune diseases, including type 1 diabetes and inflammatory bowel disease, have a suggestive association with susceptibility to RA (P <.001). Of these 6 associated loci, 2 were validated for association with RA. For rs1043099, validation significance reached. This locus exceeded genome-wide levels of significance in the combined analysis. There is also evidence in publicly functional annotation data suggesting that rs1043099 and its correlated SNPs may have regulatory activity in RA. The newly found SNP is located within a gene of unknown function, GATSL3.
“Using bioinformatics analysis, we showed that rs1043099 and its correlated SNPs have potential regulatory activity [in RA]….Further functional studies will be required to determine which of the SNPs is causal and to elucidate the mechanisms of action of each SNP,” stated Dr Eyre and colleagues.
The findings reported herein support the view that extending the size, and thus the power, of RA GWAS can lead to the discovery of new genes implicated in the development of the disease. There is hope that this accumulation of knowledge will have clinical importance in the future.