| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Rheumatology 2002; 41: 401-410
© 2002 British Society for Rheumatology
Original Papers |
Polymorphism in the immunoglobulin VH gene V1-69 affects susceptibility to rheumatoid arthritis in subjects lacking the HLA-DRB1 shared epitope
1
. Ruzicková1
Institute of Rheumatology, Na slupi 4, Prague and
1 Laboratory of Gene Expression, Charles University, Prague, Czech Republic,
2 Kennedy Institute of Rheumatology, London,
3 ARC Epidemiology Unit, Manchester and
4 Department of Immunology and the Centre for Rheumatology, University College London, London, UK
Objective. To investigate the contribution of polymorphism in the immunoglobulin heavy chain variable region V1-69 gene set to genetic susceptibility to rheumatoid arthritis (RA) in Czech and British patients.
Methods. We used V1-69 gene sequence-specific polymerase chain reaction (PCR) and restriction enzyme digestion to study polymorphism in the V1-69 gene set in germline DNA of 109 Czech and 159 British RA patients and 164 ethnically matched controls. Polymorphism was further studied by nucleotide sequencing of the V1-69 gene locus in germline DNA.
Results. We found that all patients and controls had at least one V1-69 gene copy. In the Czech RA cohort, the dimorphic nucleotide in codon 73 of V1-69 (GAA or AAA) was present in the homozygous form 73A/A in 31 of 109 (28.4%) RA patients vs 12 of 79 (15.2%) controls [odds ratio (OR)=2.22, P<0.001]. When the RA patients and controls were classified according to HLA shared epitope (SE) status, 73A/A was found in 18 of 76 (23.7%) SE+ patients compared with 13 of 38 (34.2%) SE- patients, four of 12 (18.2) SE+ controls and eight of 57 (14%) SE- controls. This suggests that homozygosity for the dimorphic sequence 73A contributed to susceptibility to RA in SE- Czech individuals (OR=3.2, P<0.001). The most striking observation was that none of the 38 SE- Czech patients, compared with 11 of 76 (14.5%) SE+ RA patients, three of 22 (13.6%) SE+ and 11 of 57 (19.3%) SE- ethnically matched controls, were homozygous for the alternative dimorphic sequence 73G/G (OR=9.1, P<0.05). These data, however, were not replicated in a Caucasoid British RA population.
Conclusion. The dimorphic sequence at codon 73 (73A/A) of the V1-69 gene contributes to genetic susceptibility in SE- Czech RA patients.
KEY WORDS: Immunoglobulins, Immunogenetics, Rheumatoid arthritis.
Correspondence to: R. A. Mageed, Department of Immunology, The Windeyer Institute of Medical Sciences, 46 Cleveland Street, London W1T 4JF, UK.