A greater variability in the 3' flanking region of the IL-6 gene in patients with systemic lupus erythematosus (SLE).

The causes of the aberrant constitutive expression of cytokines in SLE have not been elucidated yet, but alterations in cytokine gene structure could be a contributing factor. By RFLP (Restriction Fragment Length Polymorphism) analysis of genomic DNA, we found a higher incidence of allelic, higher MW XbaI bands in the IL-6 genes of 9/57 SLE patients vs 1/36 unrelated controls (p = 0.05) HLA DR/DQ typing of the polymorphic patients revealed they were all DQ beta 6. The study of one family indicated that the XbaI polymorphic patient and her polymorphic unaffected offspring had higher than normal levels of constitutive IL-6 mRNA. The SLE-associated IL-6 XbaI restriction alleles had duplications of AT-repeat sequences, approximately 500 bp downstream of the 2nd polyadenylation site, in an AT-rich mini-satellite with similarities to Matrix Associated Regions (MARs), that may be important in DNA replication and in gene expression. These are novel observations that suggest that, in SLE, there is increased variability in the 3' flanking region of the IL-6 gene. This variability may be related to the aberrant IL-6 expression that was reported by us and others in this disease.