title: Polymorphism in the immunoglobulin VH gene V1-69 affects susceptibility to rheumatoid arthritis in subjects lacking the HLA-DRB1 shared epitope.
abstract: 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(A/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, 73(A/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 11 of 57 (19.3%) SE(-) ethnically matched controls, were homozygous for the alternative dimorphic sequence 73(G/G) (OR=9.1, P<0.05). These data, however, were not replicated in a Caucasoid British RA population.
  
  
  CONCLUSIONS
  The dimorphic sequence at codon 73 (73(A/A)) of the V1-69 gene contributes to genetic susceptibility in SE(-) Czech RA patients.
authors.affiliation: Laboratory of Gene Expression, Charles University, Prague, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Vencovský
authors.forename: E
authors.initials: E
authors.lastname: Zd'árský
authors.forename: S P
authors.initials: SP
authors.lastname: Moyes
authors.forename: A
authors.initials: A
authors.lastname: Hajeer
authors.forename: S
authors.initials: S
authors.lastname: Ruzicková
authors.forename: Z
authors.initials: Z
authors.lastname: Cimburek
authors.forename: W E
authors.initials: WE
authors.lastname: Ollier
authors.forename: R N
authors.initials: RN
authors.lastname: Maini
authors.forename: R A
authors.initials: RA
authors.lastname: Mageed
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D000939:Epitopes / Q000235:genetics; D005260:Female; D005803:Genes, Immunoglobulin; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics* / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
chemical_list: D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region