Genetics of Rheumatoid Arthritis Susceptibility
Rheumatoid arthritis (RA) is a complex autoimmune disease that is influenced by genetic and environmental factors, e.g. smoking. A group of Spanish investigators around Alejandro Balsa has recently published a study about the influence of HLA DRB1 genes on the development of RA and the production of disease-specific autoantibodies (open access, free article).
They observed a dose-dependent association between SE-alleles and ACPA-titres in a Spanish cohort of RA patients.The most important genetic risk factors in RA are HLA class II molecules. There is strong evidence for an association of HLA-DRB1 alleles with a conserved amino acid sequence in the third hypervariable region of the DRβ1 chain, the so called shared epitope (SE), and susceptibility to and severity of RA.
The autoimmune origin of RA becomes visible by the presence of autoantibodies to characteristic autoantigens. The well-established rheumatoid factors (RF), i.e. antibodies directed to the Fc-region of immunoglobulins, are not specific for RA. They may occur in other diseases and in healthy elderly persons.
In contrast to that, antibodies to citrullinated proteins and peptides (ACPA) are highly specific and seem to be involved in the pathogenesis of the disease. They can be detected even years before the onset of symptoms and may predict progression to RA in patients with undifferentiated arthritis. ACPA are correlated to a more severe disease with rapid progression and a higher extent of joint destruction.
Recent studies, including the present article, have demonstrated that SE alleles are exclusively associated with ACPA-positive RA, suggesting that SE alleles may influence antigen presentation pathways leading to ACPA production and defining two different disease classes: ACPA positive and ACPA negative RA. While this predisposing correlation between ACPA production and RA is well established, the association between possibly protective alleles like HLA-DR3 or DERAA and ACPA-negative RA remained controversial.
A. Balsa et al. included 235 RA patients, 173 patients with non-rheumatoid arthritis and 269 healthy volunteers in their study. They determined titres of rheumatoid factor and ACPA in blood samples that were obtained during the patient’s first visit to the hospital before starting treatment with DMARDs. HLA class II alleles were genotyped from DNA samples obtained from peripheral blood of controls and cases.
The presence of both types of antibodies, RF and ACPA was strongly correlated with RA. An increased frequency of HLA-DRB1 alleles encoding the SE was found in RA patients compared to non-RA and control subjects. There was a dose dependent effect of SE-encoding HLA-DRB1 alleles: 30 % of RA cases and 25 % of controls had one allele, while 14 % of RA cases and 6 % of controls had two. This risk hierarchy contrasts to other studies and may be characteristic for the Spanish inception cohort.
The frequency of HLA-DR3 was lower in the RA group than in the non-RA group but similar to healthy controls. No differences in the DERAA allele distribution were observed among the three groups.
ACPA-positive RA patients showed a higher frequency of SE alleles compared to healthy controls, indicating that SE alleles contribute to ACPA production. In RA patients a dose-dependent association between the number of SE alleles and ACPA titres occurred. Patients with two alleles had significantly higher ACPA titres than those with only one allele. The presence of HLA-DR3 or DERAA encoding alleles was associated with markedly reduced ACPA levels, suggesting a protective mechanism. HLA-DR3 and HLA DERAA are related to lower levels of ACPA, this may explain their association with less severe disease.
In summary, these data show the complexity of HLA class II interactions in RA, confirming previous findings that ACPA positive RA is strongly associated with the SE with a gene-dose effect in a Spanish population.
Balsa A, Cabezon A, Orozco G, Cobo T, Miranda-Carus E, Lopez-Nevot MA, Vicario JL, Martin-Mola E, Martin J, Pascual-Salcedo D. Influence of HLA DRB1 alleles in the susceptibility of rheumatoid arthritis and the regulation of antibodies against citrullinated proteins and rheumatoid factor. Research Article. Arthritis Res Ther. 2010 Apr 6;12(2):R62. – open access, free article