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Our aim was to examine, using microsatellite (ms) markers, the contribution of the telomeric part of the HLA region to rheumatoid arthritis (RA) predisposition in the Spanish population. We have looked at the distribution of DQB1, DRBI and five ms loci (D6S1014, D6S273, D6STNFa, MIB and C1-2-5) within the HLA region in 147 Spanish RA patients and 202 control subjects. A total of 19 conserved ms configurations were observed, twelve of them in linkage disequilibrium with particular DQB1-DRB1 haplotypes. Interestingly, haplotype c1 (DQB1*0201-DRB1*0301-D6S1014*143-D6S273*139-D6STNFa*99-MIB*350-C1-2-5*196) was significantly associated with RA predisposition. As part of this haplotype, the MIB*350 allele was found to be a risk factor independently of the RA-predisposing haplotypes. The present results along with data from others prove the existence of a second predisposing locus located inside the MHC region, and suggest that might be located within the TNFa-HLA-B region.

Objective: To evaluate the contributions of HLA-DQ and -DR polymorphisms to susceptibility to rheumatoid arthritis (RA) in a population in southern Spain, and to compare the value of the shared epitope (SE) and RA protection (RAP) models in accounting for the HLA class II region's contribution to RA predisposition., Methods: One hundred sixty RA patients and 153 healthy controls were typed for HLA-DRB1 and -DQB1 using high-resolution DNA techniques. Distributions of predisposing DRB1 alleles in patients and control subjects according to the SE model were compared with distributions of predisposing DQ and protective DERAA-positive DRBI alleles according to the RAP model., Results: DQ3 (DQBI*03 and *04 combined with DQA1*03) and DQ5 (DQB1*0501/DQA1*0101) alleles predisposed individuals to RA independently of SE-positive DRB1 alleles. DQ3/3-homozygous individuals had the strongest risk of developing RA. DQ3 molecules predisposed to RA more than did DQ5 molecules. The weaker predisposition mediated by DQ5 included the DRB1*1001-carrying haplotype; no DRB1*1001-homozygous patients were observed. DRBI*0401 played a unique role in the contribution of DQ3-DR4 haplotypes to RA, in spite of its low frequency in southern Spain., Conclusion: The low prevalences of RA and of mild disease observed in Spain, and in southern Europe in general, can be explained in great part by the low frequency of DQ3-DR4 haplotypes, especially those carrying DRB1*0401. However, the overall distribution of HLA-DQ and -DR alleles in RA patients compared with control subjects is similar to that in other European and North American populations. A model involving both DQ and DR can best account for the contribution of HLA to RA.

We investigated the possible association between the IL-6 promoter polymorphisms, at positions -622 and -174, and susceptiblity to, and/or outcome of, rheumatoid arthritis (RA). A total of 163 patients with RA and 157 healthy controls were genotyped for IL-6 using a PCR-RFLP method. The -622 and -174 alleles were in complete linkage disequilibrium. No difference was observed in the distribution of IL-6 promoter genotype or allele frequencies between RA patients and controls. However, a significant difference in the mean age at disease onset between IL-6 genotypes was observed. The present data appear to rule out an important role of IL-6 promoter polymorphisms in the susceptibility to RA. However, IL-6 genotypes may contribute to the pathogenesis of the disease by influencing the age at disease onset.

Objective: To investigate a possible association of Fcgamma receptor IIIA (FcgammaRIIIA) gene polymorphism at position 158 with susceptibility to, and the outcome of, rheumatoid arthritis (RA)., Methods: One hundred seventeen RA patients and 142 unrelated healthy control subjects from the same geographic area were studied. Genotyping for FcgammaRIIIA-158V/F was performed by a method based on polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis using amplification-created restriction sites. HLA-DRB1 typing by PCR-sequence-specific oligonucleotide hybridization (reverse hybridization) was also performed., Results: Allele and genotype distributions in healthy controls were similar to those reported in other populations. The overall distribution of genotypes in the patients was significantly different from that in the controls (P = 0.023, by chi-square test from 3 x 2 contingency table). An overrepresentation of the FcgammaRIIIA-158FF genotype in the patients was observed (for 158FF versus non-158FF P = 0.01, odds ratio [OR] 1.98, 95% confidence interval [95% CI] 1.16-3.4). However, the FcgammaRIIIA-158VF genotype was increased in controls (for 158VF versus non-158VF P = 0.021, OR 0.54, 95% CI 0.32-0.92). No associations were found with any of a series of clinical parameters. Analysis of FcgammaRIIIA-158FF along with shared epitope showed that the presence of both factors increased the susceptibility to RA (P = 0.0009, OR 3.6, 95% CI 1.63-8.01); however, they probably do not interact to produce this effect., Conclusion: These results indicate that the FcgammaRIIIA-158 genotypes confer differential susceptibility to RA in our study population. Further studies to elucidate the role of this polymorphism in the pathogenesis of RA and other autoimmune diseases are warranted.

Objective: To investigate the possible association between HLA antigens and adverse reactions to gold sodium thiomalate therapy (GSTM)., Methods: Ninety consecutive patients with rheumatoid arthritis (RA) were studied for possible association between HLA antigens and adverse reactions to GSTM therapy., Results: HLA-DR5 was significantly increased in patients who developed gold induced mucocutaneous lesions. On the other hand, patients with RA carrying B8 and DR3 antigens are of a high risk of developing proteinuria after gold therapy. A very interesting finding was the low incidence of DR7 antigen in patients who developed adverse reactions to GSTM. We also report the relationship between B27 antigen and chrysiasis due to gold therapy., Conclusion: Our results support suggestions that the DR7 antigen provides a protective effect against gold toxicity. We also found a strong association between DR5 and mucocutaneous lesions in patients with RA treated with GSTM.