Influence of the HLA-DRbeta shared epitope on susceptibility to and clinical expression of rheumatoid arthritis in Chilean patients

Abstract

Objective-To analyse the influence of shared epitope positive HLA-DRB1 alleles (QKRAA or QRRAA) ) on rheumatoid arthritis (RA) susceptibility and severity in Chileans, a population that exhibits a weak association with HLA-DR4. Methods-Prevalence of alleles DRB1*01 and DRB1*04 alleles was determined by polymerase chain reaction amplification and sequence specific oligonucleotide hybridisation in 129 RA patients with defined clinical features and in 97 healthy controls. Results-The shared epitope was found in 70 (54%) of the RA patients and in 29 (30%) of controls (odds ratio (OR) =3; 95% confidence intervals (CI) = 1.5, 5.1; p = 0.0004), and was present in a double dose in 20% of patients versus 4% of controls (OR = 6; 95% CI = 2, 21; p = 0.0009). HLA-DRB1*0403 was the most prevalent DR4 subtype in controls (19%). HLA-DRB1*0404 or *0408 were the alleles most prominently associated with RA, 19% versus 6 % in controls (OR=3; 95% CI = 1.3, 10; p = 0.01). The risk of RA in those carrying a double dose of the shared epitope was 7.5 times that seen in patients lacking the epitope. Disease severity was moderate: 33% had extra-articular manifestations. The double dose was associated with an increased risk of vasculitis or extra-articular manifestations. However, 59 patients (46%) did not carry the shared epitope and 18 of them (31%) had extra-articular manifestations. Conclusions-The weak association of RA with DR4 in Chileans seems to relate to a relatively high frequency of the DRB1*0403 allele among DR4 subtypes. As in other populations, the shared epitope in double dose is associated with RA development, especially in its more severe forms. However, both development and expression of severe forms of the disease were independent of the shared epitope in a high proportion of patients, thus emphasising the genetic heterogeneity of the disease and the possible involvement of other genetic elements.

Rheumatoid arthritis association in Colombian population is restricted to HLA-DRB1*04 QRRAA alleles

“…Thus, in our population RA is linked to HLA-DRB1*04-QRRAA alleles. As previously reported, 5 we observed a gene dosage effect in the association of the SE with RA (Table 3). This was a cross-sectional study in which the sample size as well as the low number of positive patients for extra-articular manifestations precludes an analysis to test the severity with respect to SE.…”

“…3,4 Few studies of human leukocyte antigen (HLA) and RA have been done in South-Americans. [5][6][7] However, in Colombians, the association of the SE and RA has not been pre- viously investigated. Therefore, we examined the influence of SE on the susceptibility of RA in a northwestern Colombian population (Medellin), whose ancestral origin is more Caucasian with low Amerindian or Negroid contributions.…”

“…In Chilean patients from Santiago, the most frequently expressed DRB1 alleles were DRB1* 0404 or DRB1*0408. 5 However it was demonstrated that in 46% of the cases the susceptibility towards disease and its severity were independent of the SE. 5 In Argentinean patients from Buenos Aires, susceptibility to RA was associated with DRB1*0404 but the SE alleles failed to correlate with more severe disease with the exception of DRB1*1001 which, although infrequent, was significantly associated with radiological damage.…”

“…5 However it was demonstrated that in 46% of the cases the susceptibility towards disease and its severity were independent of the SE. 5 In Argentinean patients from Buenos Aires, susceptibility to RA was associated with DRB1*0404 but the SE alleles failed to correlate with more severe disease with the exception of DRB1*1001 which, although infrequent, was significantly associated with radiological damage. 6 In Peruvians patients from Lima, a weak association of disease susceptibility with DRB1*1402 was reported, but the SE did not influence disease severity.…”

Smoking promotes exacerbated inflammatory features in dendritic cells of Chilean rheumatoid arthritis patients

“…Supporting this hypothesis, a recent study performed in transgenic mice lacking endogenous MHC-II and bearing the human RA-associated alleles HLA-DRB1*0401 or DQA1*0301/DQB1*0302 showed that exposition of HLA-DRB1*0401-bearing mice to cigarette smoke reduces CIA severity, whilst DQA1*0301/DQB1*0302-bearing mice exposed to cigarette smoke exacerbated CIA manifestation 30 . Studies in Chilean RA-patients show high frequency of the HLA-DRB1*0403 allele 31 , which could account for the differences observed.…”