Polymorphism in the immunoglobulin VH gene V1‐69 affects susceptibility to rheumatoid arthritis in subjects lacking the HLA‐DRB1 shared epitope

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 73 AA 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, 73 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 73 A 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 I I of 57 (19.3%) SE ethnically matched controls, were homozygous for the alternative dimorphic sequence 73 GG (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 (73 A A ) of the V1-69 gene contributes to genetic susceptibility in SE Czech RA patients.