title: Validation of the reshaped shared epitope HLA-DRB1 classification in rheumatoid arthritis.
abstract: Recently, we proposed a classification of HLA-DRB1 alleles that reshapes the shared epitope hypothesis in rheumatoid arthritis (RA); according to this model, RA is associated with the RAA shared epitope sequence (72-74 positions) and the association is modulated by the amino acids at positions 70 and 71, resulting in six genotypes with different RA risks. This was the first model to take into account the association between the HLA-DRB1 gene and RA, and linkage data for that gene. In the present study we tested this classification for validity in an independent sample. A new sample of the same size and population (100 RA French Caucasian families) was genotyped for the HLA-DRB1 gene. The alleles were grouped as proposed in the new classification: S1 alleles for the sequences A-RAA or E-RAA; S2 for Q or D-K-RAA; S3D for D-R-RAA; S3P for Q or R-R-RAA; and X alleles for no RAA sequence. Transmission of the alleles was investigated. Genotype odds ratio (OR) calculations were performed through conditional logistic regression, and we tested the homogeneity of these ORs with those of the 100 first trio families (one case and both parents) previously reported. As previously observed, the S2 and S3P alleles were significantly over-transmitted and the S1, S3D and X alleles were under-transmitted. The latter were grouped as L alleles, resulting in the same three-allele classification. The risk hierarchy of the six derived genotypes was the same: (by decreasing OR and with L/L being the reference genotype) S2/S3P, S2/S2, S3P/S3P, S2/L and S3P/L. The homogeneity test between the ORs of the initial and the replication samples revealed no significant differences. The new classification was therefore considered validated, and both samples were pooled to provide improved estimates of RA risk genotypes from the highest (S2/S3P [OR 22.2, 95% confidence interval 9.9-49.7]) to the lowest (S3P/L [OR 4.4, 95% confidence interval 2.3-8.4]).
authors.affiliation: GenHotel-EA 3886, University Evry-ParisVII Medical School, Member of the Autocure European Consortium, Evry-Genopole, France. michou@polyarthrite.net
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Michou
authors.forename: Pascal
authors.initials: P
authors.lastname: Croiseau
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Petit-Teixeira
authors.forename: Sophie Tezenas
authors.initials: ST
authors.lastname: du Montcel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lemaire
authors.forename: Céline
authors.initials: C
authors.lastname: Pierlot
authors.forename: José
authors.initials: J
authors.lastname: Osorio
authors.forename: Wafa
authors.initials: W
authors.lastname: Frigui
authors.forename: Sandra
authors.initials: S
authors.lastname: Lasbleiz
authors.forename: Patrick
authors.initials: P
authors.lastname: Quillet
authors.forename: Thomas
authors.initials: T
authors.lastname: Bardin
authors.forename: Bernard
authors.initials: B
authors.lastname: Prum
authors.forename: Françoise
authors.initials: F
authors.lastname: Clerget-Darpoux
authors.forename: François
authors.initials: F
authors.lastname: Cornélis
mesh_terms: D001172:Arthritis, Rheumatoid / Q000145:classification* / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005602:France / Q000208:ethnology; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D010290:Parents; D012044:Regression Analysis; D015203:Reproducibility of Results; D044465:White People
chemical_list: D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains