An endogenous retroviral long terminal repeat at the HLA-DQB1 gene locus confers susceptibility to rheumatoid arthritis

Human endogenous retrovirus (HERV) long terminal repeat (LTR) elements cont ain regulatory sequences that can influence the expression of adjacent cell ular genes, which may contribute to breakdowns of the immune function leadi ng to autoimmune disease. Rheumatoid arthritis (RA) is associated with part icular HLA-DR/DQ haplotypes that modulate the pathogenesis of this autoimmu ne disease. We have therefore studied a solitary LTR element (DQ-LTR3) of t he HERV-K family at the HLA-DQB1 locus for a possible disease association a mong 228 RA patients and 311 unrelated blood donors. The DQ-LTR3 was signif icantly more frequent among patients (76% vs 13%, OR = 5.07,p < 0.0001), wi th the majority of patients being heterozygous for che DQ-LTR3 (61% vs 22%, p < 0.0001). HLA-DRB1*04 positive patients did still differ for the presen ce of the DQ-LTR3 (88% vs 70%, OR = 3.03,p < 0.001), with an increase of bo th DQ-LTR3 homozygous and heterozygous patients, when compared to DRB1*04 p ositive controls (p = 0.0015). HLA-DR/DQ genotype analysis among HLA-DRB1*0 4 positive individuals revealed significantly more DQ-LTR3 homozygotes amon g HLA-DRB1*04-DQB1*03 homozygous patients (72% vs 27%, p = 0.015), and the number of DQ-LTR3 homozygous (23% vs 19%) and heterozygous (66% vs 53%) ind ividuals was also increased among HLA-DRB1*04 heterozygous patients (p = 0. 034). The presence of the DQ-LTR3 element increased both the relative risk and the positive predictive value for either DRB1*04-DQB1*03 positive/negat ive individuals when compared to the presence of HLA-DRB1*04-DQB1*03 alone. In conclusion, these data suggest that this DQ-LTR3 enhances susceptibilit y to RA. (C) American Society for Histocompatibility and Immunogenetics, 19 99 Published by Elsevier Science Inc.