HLA-DRB1 alleles and shared amino acid sequences in disease susceptibility and severity in patients from eastern France with rheumatoid arthritis.
OBJECTIVE
To examine the effects of HLA-DRB1 alleles and amino acid sequences that carry the shared epitope (SE) upon rheumatoid arthritis (RA) susceptibility and disease severity in patients from Eastern France.


METHODS
HLA-DRB1 alleles were determined in 120 patients and 104 healthy controls by polymerase chain reaction/sequence specific oligonucleotide probes. Subtyping of DRB1*01 and *04 were performed using sequence specific primers. Patients were retrospectively evaluated for disease duration, age at disease onset, presence of rheumatoid factors, subcutaneous nodules, vasculitis and other extraarticular diseases, for the need for arthroplasty and immunosuppressive/immunoregulatory agents, and for radiographic damage.


RESULTS
The prevalence of HLA-DRB1*04 was significantly higher in patients (46.6%) than in controls (17.3%) (Pcorr = 0.000003). HLA-DRB1*0101 and *0401 were the most prominently associated subtypes in patients with RA (33.3%, Pcorr = 0.011, and 28.3%, Pcorr = 0.00008, respectively). A significant fraction of patients (72.5%) expressed one or 2 copies of the SE (p < 0.0000001; OR 4.77, CI 2.61-8.78). The presence of double SE was associated with a higher risk of developing RA (OR 4.83, CI 1.91-12.71; p = 0.0001). No significant differences in the clinical records among patients expressing no RA linked alleles, one and 2 copies of the SE, were observed. However, analyzing the specific effect of each amino acid sequence, we observed a significant association of the QKRAA motif with vasculitis (p = 0.03) and history of joint replacement surgery (p = 0.05), suggesting a role for lysine in position 71 of the shared sequence.


CONCLUSIONS
These findings differ from those of previous HLA-DRB1 allele studies in patients with RA from other regions of France. Thus, the heterogeneity in both the expression of DRB1 alleles and the association of these alleles with disease severity could be relevant within a country such as France.
Department of Rheumatology, University Hospital, Besançon, France.
E
E
Toussirot
B
B
Auge
P
P
Tiberghien
J
J
Chabod
J P
JP
Cedoz
D
D
Wendling
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000595:Amino Acid Sequence; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D000939:Epitopes / Q000235:genetics; D005260:Female; D005602:France; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006684:HLA-DR Antigens / Q000737:chemistry / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012720:Severity of Illness Index
D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains