Distribution of HERV-LTR elements in the 5 '-flanking region of HLA-DQB1 and association with autoimmunity

We established the detailed polymorphism of the 5'-flanking region and the first exon of the human leukocyte antigen (HLA)-DQB1 alleles. One hundred a nd forty-five Spanish rheumatoid arthritis (RA) patients and 200 healthy vo luntary blood donors from southern Spain along with 42 B-cell lines were an alyzed for the presence of the retrovirus-derived long terminal repeats (LT Rs) LTR3, LTR5, and LTR13. LTR3 positivity was always associated with certa in DQB1 alleles, i.e., *0302, *0402, *0601, *0202, and *0305. Sequencing an alysis of the 5'-flanking region of DQB1*0301, *0303 and *0502 alleles in h omozygous 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 DQ B1 alleles and a lack of stratification for HLA typing explain previously r eported associations of the LTR3 element with RA and type I diabetes (IDDM) . LTRS showed identical distribution to LTRS, consistent with a previously suggested LTR3-LTR5 tandem arrangment. 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 c arrying them. LTR elements are known to regulate gene expression. Therefore , a possible involvement of LTR13 in the association of DPB1*0302, *0303, a nd *0402 with IDDM requires further investigation. The sequencing results o f the DQB1 first exon demonstrated that DPB1*0601 was generated by a recomb ination 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.