Genetics of Rheumatoid Arthritis — A Comprehensive Review

Abstract

The “Bermuda triangle” of genetics, environment and autoimmunity is involved in the pathogenesis of rheumatoid arthritis (RA). Various aspects of genetic contribution to the etiology, pathogenesis and outcome of RA are discussed in this review. The heritability of RA has been estimated to be about 60 %, while the contribution of HLA to heritability has been estimated to be 11–37 %. Apart from known shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, other HLA alleles, such as HLA-DRB1*13 and DRB1*15 have been linked to RA susceptibility. A novel SE classification divides SE alleles into S1, S2, S3P and S3D groups, where primarily S2 and S3P groups have been associated with predisposition to seropositive RA. The most relevant non-HLA gene single nucleotide polymorphisms (SNPs) associated with RA include PTPN22, IL23R, TRAF1, CTLA4, IRF5, STAT4, CCR6, PADI4. Large genome-wide association studies (GWAS) have identified more than 30 loci involved in RA pathogenesis. HLA and some non-HLA genes may differentiate between anti-citrullinated protein antibody (ACPA) seropositive and seronegative RA. Genetic susceptibility has also been associated with environmental factors, primarily smoking. Some GWAS studies carried out in rodent models of arthritis have confirmed the role of human genes. For example, in the collagen-induced (CIA) and proteoglycan-induced arthritis (PgIA) models, two important loci — Pgia26/Cia5 and Pgia2/Cia2/Cia3, corresponding the human PTPN22/CD2 and TRAF1/C5 loci, respectively — have been identified. Finally, pharmacogenomics identified SNPs or multiple genetic signatures that may be associated with responses to traditional disease-modifying drugs and biologics.

Role of citrullination modification catalyzed by peptidylarginine deiminase 4 in gene transcriptional regulation

“…In addition, high levels of PADI4 protein are expressed in the inflamed synovium of RA patients [50][51][52][53][54][55][56]. The role of PADI4 in early RA pathogenesis is mainly through promoting the generation of citrullinated autoantigens [57,58].…”

CD24: from a Hematopoietic Differentiation Antigen to a Genetic Risk Factor for Multiple Autoimmune Diseases

“…The transcription factor SP1 binds to the risk allele and facilitates CD24 transcription. TSS transcription start site, MS multiple sclerosis complex and is thought to involve genetic and environmental factors [112,113].…”

Insight into the Mechanism of SDS Irritation on Human Skin Keratinocytes by Examination of Changes in Gene Expression

“…As HLA is located in the upstream part of the rheumatoid arthritis pathways, expression changes in HLA will trigger changes in expression in downstream genes in this pathway. HLA molecules play a crucial role in the detection and elimination of virally infected cells [11], and HLA is estimated to contribute 37% to the genetic variability of rheumatoid arthritis [12]. To summarize, all of CCL5, IL-6, FOS, CSF1, and HLA showed significant changes in expression after 0.5 h of SDS stimulation and participate in the rheumatoid arthritis pathway to cause proinflammatory reaction and autoimmune activation.…”