A TAQI POLYMORPHISM IN THE HUMAN INTERLEUKIN-1-BETA (IL-1-BETA) GENE CORRELATES WITH IL-1-BETA SECRETION INVITRO

In the present study we searched for restriction fragment length polymorphisms (RFLP) in the human interleukin-1-beta (IL-1-beta) gene and for correlations to monocyte (Mo) function in non-related healthy donors and insulin-dependent diabetic patients. We demonstrated a diallelic polymorphism with the restriction enzyme TaqI consisting of fragments of 9.4 kb and 13.4 kb. No differences in allele or genotype frequencies of this RFLP were observed between randomly selected controls and randomly selected patients with insulin-dependent diabetes mellitus (IDDM). However, when analysing IDDM patients negative for HLA-DR3 and -DR4, our data demonstrate that the 13.4 kb allele is more frequent in this group compared to a matched control group. The functional impact of this RFLP was studied by analysing in vitro stimulated Mo IL-1-beta response. An IL-1-beta allele dosage effect on secretory capacity was observed after LPS-stimulation: 13.4/13.4 kb homozygous individuals secreted significantly more IL-1-beta than 9.4/13.4 kb heterozygous individuals, who secreted significantly more than 9.4/9-4 kb homozygous individuals. Analyses of supernatants from LPS-stimulated Mo cultures from individuals with each TaqI IL-1-beta genotype revealed no differences in the mouse thymocyte co-stimulatory assay when compared on a molar basis, indicating that the TaqI polymorphism gave rise only to quantitative differences in expression levels and probably not to a mutant IL-1-beta. We conclude that the 13.4 kb allele represents an IL-1-beta 'high-secretor' phenotype, that the observed RFLP may be a genetic susceptibility marker for IDDM in non-DR3 and non-DR4 individuals and that high IL-beta secretory capacity may be a pathogenic factor for IDDM in these patients.