Genetics of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease involving symmetric joints and is generally characterized by persistent pain, tenderness, and destruction of joints. The vast majority of RA patients produce autoantibodies, and immune cell involvement in disease development is well recognized, as is the contribution of other types of cells in synovial tissue, like fibroblasts. It is known that there are major genetic associations with the HLA locus, while multiple non-HLA genetic variants display relatively low risk of RA. Both HLA and non-HLA associations suggest that the profiles of genetic associations for autoantibody-positive vs. autoantibody-negative RA are different. Several alleles of HLA-DRB1 are associated with high risk for autoantibody-positive RA, with the strongest risk characterized by valine at position 11 of the protein sequence (HLA-DRB1*04 and *10 alleles). There is a strong protective effect for the risk of autoantibody-positive RA associated with HLA-DRB1*13 alleles. Although major genetic associations have been known for several years, understanding of the specific mechanisms in the development of increased risk of RA for these variations is work in progress. Current studies focus on the binding of immune receptors involved in recognition of putative peptides in activation of T cells, as well as investigation of cell signaling mechanisms. At least a part of RA risk could be explained by gene–gene and gene-environment interactions. There are currently more than 150 candidate loci with polymorphisms that associate with RA, mainly related to seropositive disease, and new discoveries are anticipated in the future from investigation of diverse human populations. This new research will help create a strong foundation for the continuing process of integrating genetic, epigenetic, transcriptomic, and proteomic data in studies of RA.

Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study

“…Genetic association estimates for seropositive and seronegative RA were taken from a published study of RA (21) that reported separate genome-wide association studies (GWAS) of seropositive (18,019 cases and 991,604 controls) and seronegative (8,515 cases and 1,015,471 controls) RA. One hundred and thirty-five autosomal single nucleotide polymorphisms (SNPs) that were associated with RA (either seropositive, seronegative or both) in previous GWAS of European ancestry or multi-ancestry were selected as IVs for RA (22). These IVs were used for testing the causal effect of RA as the exposure and on IPF as the outcome.…”

Genetics and functional genetics of autoimmune diseases

“…Naito et al [7] presents current fine-mapping efforts to dissect causal HLA variants of autoimmune diseases. Then, Ha et al [8], Padyukov et al [9], Kim et al [10], and Márquez et al [11] summarize recent achievements in genetics of four major autoimmune diseases of systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes, respectively. More than a hundred of risk variants have been massively identified for these autoimmune diseases through active international collaboration networks.…”

MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in rheumatoid arthritis

“…), dysregulated immune cells (such as B cells, CD4 + T cells, etc. ), and excessive systemic inflammation contribute to RA development and progression ( 6 – 8 ).…”