Expression of QK/QR/RRRAA or DERAA motifs at the third hypervariable region of HLA-DRB1 and disease severity in rheumatoid arthritis.
OBJECTIVE
To examine the relationship between disease severity in patients with confirmed rheumatoid arthritis (RA) and the carriage of alleles expressing the high risk epitope (HRE) QK/QR/RRRAA or the low risk epitope (LRE) DERAA at positions 70-74 of the third hypervariable region of HLA-DRB1.


METHODS
A case-control design to compare allele carriage rates in 204 Caucasian subjects with severe RA and mild RA and healthy controls. Patients had a mean disease duration of 12-18 years and severity of RA was defined using clinical and therapeutic criteria. Molecular typing at the HLA-DRB1 locus was performed using a polymerase chain reaction method.


RESULTS
Eighty-seven percent of patients (52/60) with severe RA had one or more of the alleles bearing the QK/QR/RRRAA motif or HRE, compared with 54% (21/39) with mild RA (OR 5.57, p = 0.0007) and 39% (41/105) of controls (OR 10.15, p < 0.0001). Twenty-five percent of patients (15/60) with severe disease expressed 2 disease associated HRE DRB1 alleles, compared with 13% of patients (5/39) with mild disease (OR 2.3, p = NS) and 5% (5/105) of controls (OR 6.67, p = 0.0003). In contrast, only 5% of patients (3/60) with severe RA expressed one of the LRE alleles that carry the DERAA motif at positions 70-74, compared with 31% of patients (12/39) with mild RA (OR 0.12, p = 0.0013) and 22% of controls (23/105) (OR 0.19, p = 0.0082). No patient or control was homozygous for LRE alleles. Eighty-three percent (50/60) of patients with severe RA expressed the HRE without the LRE, compared with 44% (17/39) of those with mild disease (OR 6.47, p < 0.0001) and 35% (37/105) of controls (OR 9.19, p < 0.0001). In contrast, only one patient (2%) with severe disease expressed the LRE without the HRE, compared with 20% (8/39) of those with mild disease (OR 0.07, p = 0.0047) and 16% (17/105) of controls (OR 0.09, p = 0.009). There was no significant difference between the 3 groups in the frequency of patients who expressed both or neither epitope. Logistic regression showed that age at disease onset (p = 0.0009), duration of disease (p = 0.007), positive rheumatoid factor status (p = 0.003), and presence of the HRE or LRE (p = 0.00005) were significantly associated with the presence of severe disease.


CONCLUSIONS
HLA-DRB1 alleles appear to confer an important bidirectional influence on the risk of disease severity in RA, with 20-fold difference in OR between those associated with the highest (HLA-DRB1*0401) and lowest (HLA-DRB1*1301/02) risk. The HRE and LRE exhibit diametrically opposed effects, which may be mutually antagonistic. These data support a multistep pathogenesis in which MHC class II genes are one component of a coordinate genetic and environmental interaction leading to immunological injury and joint destruction.
Department of Medicine, Vancouver General Hospital, Mary Pack Arthritis Centre, Vancouver British Columbia, Canada.
Abbas
A
Khani-Hanjani
Diane
D
Lacaille
Cathy
C
Horne
Andrew
A
Chalmers
David I
DI
Hoar
Robert
R
Balshaw
Paul A
PA
Keown
D000328:Adult; D000368:Aged; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*; D016022:Case-Control Studies; D015331:Cohort Studies; D000939:Epitopes; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006683:HLA-DQ Antigens / Q000032:analysis*; D006684:HLA-DR Antigens / Q000032:analysis* / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index
D000939:Epitopes; D005819:Genetic Markers; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen