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The heat shock 60-kDa protein 1 (HSP60) is involved in immune and inflammatory reactions, which are hallmarks of rheumatoid arthritis (RA). HSP60 is encoded by the HSPD1 gene located on 2q33, one of the suggested RA susceptibility loci in the French Caucasian population. Our aim was to test whether HSPD1 is a major susceptibility gene by studing families from the French Caucasian population. Three single nucleotide polymorphisms (SNPs) were studied in 100 RA trio families, and 100 other families were used for replication. Genetic analyses were performed by comparing allelic frequencies, by applying the transmission disequilibrium test, and by assessing the genotype relative risk. We observed a significant RA association for the C/C genotype of rs2340690 in the first sample. However, this association was not confirmed when the second sample was added. The two other SNPs and the haplotype analysis did not give any significant results. We conclude that HSPD1 is not a major RA susceptibility gene in the French Caucasian population.

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]).