Immunogenetic risks of anti-cyclical citrullinated peptide antibodies in a North American Native population with rheumatoid arthritis and their first-degree relatives.
OBJECTIVE
To determine the prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies in unaffected relatives of North American Native probands with rheumatoid arthritis (RA); and the associations of the shared epitope (SE) and HLA-DRB1*0901 with RA and anti-CCP antibodies.


METHODS
The subjects were RA probands, affected relatives, unaffected first-degree (FDR) and more distant relatives, and unaffected controls from the same population. HLA-DRB1 typing was determined by DNA sequencing and anti-CCP antibodies were determined by ELISA.


RESULTS
DRB1*0901, SE, and SE/DRB1*0901 genotypes were all associated with RA. SE/DRB1*0901, but not other SE genotypes, was associated with disease onset at age<16 years. The frequency of anti-CCP antibodies was 82% in RA probands, 17% in FDR, 11% in more distant relatives, and 3% in controls. Among unaffected relatives, a significant increased risk of anti-CCP was associated with SE/DRB1*0901 genotype, but not with SE.


CONCLUSIONS
An independent association of the non-SE allele DRB1*0901 with RA was confirmed in this population, and this allele in combination with a SE allele was associated with younger age at disease onset. FDR of RA probands have a higher prevalence of anti-CCP antibodies than more distant relatives and unrelated controls, suggesting a gradient of risk for disease development. Immunogenetic risks may act early in disease pathogenesis at the level of initiation of RA autoantibody formation; however, it is not clear what additional genetic and environmental risks are involved in progression to clinical disease.
Department of Medicine, University of Manitoba Arthritis Centre, RR149 - 800 Sherbrook Street, Winnipeg, Manitoba R3A 1M4, Canada. elgabalh@cc.umanitoba.ca
Hani S
HS
El-Gabalawy
David B
DB
Robinson
Donna
D
Hart
Brenda
B
Elias
Janet
J
Markland
Christine A
CA
Peschken
Irene
I
Smolik
Gabriela
G
Montes-Aldana
Marlis
M
Schroeder
Marvin J
MJ
Fritzler
Mary
M
Cheang
Kiem
K
Oen
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000208:ethnology / Q000235:genetics* / Q000276:immunology*; D002170:Canada / Q000453:epidemiology; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D007198:Indians, North American; D008297:Male; D010456:Peptides, Cyclic / Q000276:immunology*; D017422:Sequence Analysis, DNA
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide