The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis.
OBJECTIVE
To explore the role of HLA-DRB1 genes in determining disease severity in rheumatoid arthritis.


METHODS
Case series of patients with seropositive rheumatoid arthritis.


METHODS
The outpatient clinic of the Division of Rheumatology, Mayo Clinic.


METHODS
One hundred and two patients with seropositive, erosive rheumatoid arthritis and a minimum disease duration of 3 years.


METHODS
Patients were genotyped for both HLA-DRB1 alleles and were categorized according to the expression of one or two disease-linked HLA-DRB1 alleles. Identification of HLA-DRB1 alleles was done by the polymerase chain reaction and subsequent oligonucleotide hybridization. Homozygosity for allelic variants was confirmed by sequence analysis. Immunogenetically defined patient subgroups were retrospectively evaluated for joint destruction and patterns of disease manifestation, including rheumatoid organ disease.


RESULTS
Of 102 patients, 98 (96%) expressed the disease-linked sequence polymorphism. Forty-seven patients (46%) carried a double dose of the relevant sequence stretch: Twenty-eight patients expressed HLA-DRB1*04 variants on both alleles, and 19 combined an HLA-DRB*04 variant with HLA-DRB1*0101 or DRB1*1402. Nodular disease was present in 100% of patients typed as HLA-DRB1*04/04 and in 59% of patients typed as HLA-DRB1*04 and who had inherited only a single dose of the disease-linked sequence polymorphism (P < 0.0001). Major organ systems were involved in 61% and 11% of these two patient groups, respectively (P < 0.0001); and joint surgery was required in 61% and 25% (P < 0.002), respectively. Patients typed as HLA-DR*04/01 had intermediate clinical courses.


CONCLUSIONS
Genotyping patients with rheumatoid arthritis for both HLA-DRB1 alleles identifies clinical subsets with distinct profiles of disease manifestations.
Weyand
C M
CM
Mayo Clinic and Foundation, Rochester, Minnesota.
Hicok
K C
KC
Conn
D L
DL
Goronzy
J J
JJ
D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D001483:Base Sequence; D016009:Chi-Square Distribution; D005260:Female; D015870:Gene Expression; D005819:Genetic Markers / Q000276:immunology; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D012189:Retrospective Studies; D012720:Severity of Illness Index
D005819:Genetic Markers; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II