New Analysis Identifies Biomarker for Rheumatoid Arthritis Risk


The new study, based on an analysis of existing literature and a replication cohort, helps clarify the role of a variant in microRNA-146a.

A new study suggests patients with a specific genetic variant are more likely to be diagnosed with rheumatoid arthritis (RA), though the authors said it is not yet clear exactly what role the variant plays in the pathogenesis of the disease.

Writing in the Annals of Medicine, corresponding author of Rui-Xue Leng, MD, of Anhui Medical University, and colleagues, explained that the small noncoding RNA microRNA-146a (miR146-a) has already been linked with immune responses and autoimmunity, prompting investigators to question whether single nucleotide polymorphisms (SNPs) in the miR-146a gene might be related to susceptibility for certain autoimmune diseases.

One possibility, they noted, was that miR-146a polymorphisms heighten risk for RA. The question has been studied with mixed results, so Leng and colleagues embarked to carry out a more comprehensive analysis, using existing literature and their own replication study.

The investigators identified 3 previous genome-wide association studies (GWASs) of patients with RA. The studies included European populations, Korean and Japanese patients, and Chinese patients, which together involved more than 20,000 people with RA and more than 60,000 controls. For the replication study, Leng and colleagues recruited 779 patients with RA and 1809 controls. Patients were excluded from the analysis if they had other autoimmune diseases, mental health conditions, or chronic severe non-communicable diseases or systemic infections.

Analysis of the genetic data confirmed that SNP rs2431697 was linked with the risk of RA.

“The extracted genetic association data from 3 previous GWASs showed that the allele T of functional SNP rs2431697 increased RA susceptibility,” the investigators concluded.

However, they noted that the effect was larger in the Asian populations studied (Asian meta-analysis: odds ratio [OR], 1.15; 95%CI, 1.09-1.22, P = 4.37E-07; trans-ethnic meta-analysis: OR, 1.07; 95%CI, 1.04–1.10, P = 1.79E-06).

“The cytokine assay also showed that the risk allele T of the SNP rs2431697 is inversely associated with plasma TNF-α levels in healthy controls (p = .016),” the authors added.

Leng and colleagues suggested this might be due to reverse causality, noting that earlier research has suggested TNF-α stimulation resulted in upregulation of miR-146a expression in Jurkat T cells and human CD4+ T cells.

Comparing their findings to the existing literature, the investigators said the large scale and the different populations included in the analysis give credibility to their findings, as did their ability to confirm the results of their GWAS analysis in their replication cohort. However, they also noted a couple of limitations to their research, including the unavailability of individual data in the GWASs, and a lack of data about indicators such as extra-articular manifestations and joint erosions within their replication study cohort.

The results of the study could be an important milestone in efforts to understand risk of RA, as investigators continue to search both for biomarkers of disease risk and for biomarkers that could suggest optimal treatments.

“In summary, our data firstly supported that the SNP rs2431697 in miR-146a gene correlates with susceptibility of RA,” the authors concluded. “The detailed mechanism of the loci in the pathogenesis of RA needs to be further studied.”


Zhang LL, Wu XX, Wang XF, et al. Genetic variant in microRNA-146a gene is associated with risk of rheumatoid arthritis. Ann Med. 2021;53(1):824-829. doi:10.1080/07853890.2021.1933163

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