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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.

We established the detailed polymorphism of the 5'-flanking region and the first exon of the human leukocyte antigen (HLA)-DQB1 alleles. One hundred and forty-five Spanish rheumatoid arthritis (RA) patients and 200 healthy voluntary blood donors from southern Spain along with 42 B-cell lines were analyzed for the presence of the retrovirus-derived long terminal repeats (LTRs) LTR3, LTR5, and LTR13. LTR3 positivity was always associated with certain DQB1 alleles, i.e., *0302, *0402, *0601, *0202, and *0305. Sequencing analysis of the 5'-flanking region of DQB1*0301, *0303 and *0502 alleles in homozygous B-cell lines showed the absence of LTR3 and a massive deletion of 5635 base pairs. The undetected deletion in the flanking region of some DQB1 alleles and a lack of stratification for HLA typing explain previously reported associations of the LTR3 element with RA and type I diabetes (IDDM). LTR5 showed identical distribution to LTR3, consistent with a previously suggested LTR3-LTR5 tandem arrangement. LTR13 positivity was associated with DQB1*0302, *0303, and *0402 alleles. Distributions of the LTR elements in all B-cell lines, RA patients, and controls could be explained entirely by linkage disequilibrium with DQB1 alleles, independently of the haplotypes carrying them. LTR elements are known to regulate gene expression. Therefore, a possible involvement of LTR13 in the association of DQB1*0302, *0303, and *0402 with IDDM requires further investigation. The sequencing results of the DQB1 first exon demonstrated that DQB1*0601 was generated by a recombination event between a DR53 and a non-DR53 haplotype. Our results shed new light on the phylogeny of the HLA region and the possible contribution of DQB1 to susceptibility to autoimmunity.

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.