RESEARCH - Validation of the reshaped shared epitope HLA-DRB1 classification in RA

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Validation of the Reshaped Shared Epitope HLA-DRB1 Classification in

Rheumatoid Arthritis

Posted 05/18/2006

Laëtitia Michou; Pascal Croiseau; beth Petit-Teixeira; Sophie Tezenas

du Montcel; Isabelle Lemaire; Céline Pierlot; José Osorio; Wafa Frigui;

Lasbleiz; Quillet; Bardin; Bernard Prum; Françoise

Clerget-Darpoux; François Cornélis; the European Consortium on Rheumatoid

Arthritis Families

Abstract and Introduction

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 RR-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]).

Read the full article here:

http://www.medscape.com/viewarticle/531791

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