From the Guidelines
Rheumatoid arthritis (RA) is not directly inherited, but there is a significant genetic component that increases susceptibility, as evidenced by the presence of serum autoantibodies and specific genetic risk factors in first-degree relatives (FDRs) and indigenous populations 1. The genetic risk factors, such as the HLA-DRB1 gene, particularly the shared epitope encoding allele HLA-DRB1*1402, play a crucial role in increasing the susceptibility to RA, especially in indigenous populations 1. Some key points to consider include:
- The presence of serum autoantibodies, such as anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF), in FDRs and indigenous populations, which are associated with an increased risk of developing RA 1.
- The influence of environmental factors, such as smoking, infections, or hormonal changes, which can trigger RA in genetically susceptible individuals.
- The importance of studying asymptomatic at-risk populations, including FDRs and genetically predisposed indigenous populations, to better understand the pathobiology of RA and the influence of specific risk factors on disease progression 1. Overall, while there is a genetic component to RA, it is not directly inherited, and environmental factors play a significant role in triggering the disease in susceptible individuals.
From the Research
Genetics of Rheumatoid Arthritis
- Rheumatoid Arthritis (RA) is a complex disease with a significant genetic component, estimated to be around 60% heritable 2, 3.
- The genetic contribution to RA involves multiple genes, including HLA class II genes, which have been associated with an increased risk of developing the disease 2, 3.
- Specific HLA alleles, such as HLA-DRB101 and DRB104, have been linked to RA susceptibility, particularly in seropositive RA 2.
- Non-HLA genes, including PTPN22, IL23R, TRAF1, CTLA4, IRF5, STAT4, CCR6, and PADI4, have also been associated with RA susceptibility 2.
Heritability and Disease Severity
- The heritability of RA has been estimated to be around 60%, with HLA genes contributing 11-37% to this heritability 2.
- Genetic markers have been identified as predictors of disease severity, with substantial heritability of erosive progression rates 4.
- However, better prognostic biomarkers are still needed to predict who will develop severe disease 4.
Genetic Variants and Treatment Response
- Genetic variants have been associated with variation in treatment response or toxicity, and may be used to guide treatment strategy 3.
- Pharmacogenomics has the potential to improve patient experience and quality of life, as well as reduce healthcare costs 3.
- Large-scale Genome-Wide Association Studies (GWAS) and meta-analyses have revealed common disease-associated variants in the population that may contribute cumulatively to RA pathogenesis 3.