Influence of the HLA-DR beta shared epitope on susceptibility to and clinical expression of rheumatoid arthritis in Chilean patients.
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*0403 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.
González
A
A
Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
Nicovani
S
S
Massardo
L
L
Aguirre
V
V
Cervilla
V
V
Lanchbury
J S
JS
Jacobelli
S
S
D000328:Adult; D000368:Aged; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000276:immunology*; D002677:Chile / Q000453:epidemiology; D004198:Disease Susceptibility; D005260:Female; D006684:HLA-DR Antigens / Q000235:genetics*; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; D006720:Homozygote; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D015995:Prevalence; D012307:Risk Factors
D006684:HLA-DR Antigens; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains