Roles of functional polymorphisms in the interleukin-18 gene promoter in sarcoidosis

Background and aim of the work: Interieukin (IL)-18 plays important roles in sarcoidosis by inducing interferon-gamma in synergy with IL-12. Results of case-control studies on the association between sarcoidosis and single nucleotide polymorphisms (SNPs) in the IL-18 gene promoter are conflicting. We reexamined the association and evaluated the clinical significance of the SNPs in sarcoidosis. Methods: Genotyping of three SNPs, -137G/C, - 607 C/A, and -656 G/T, in the IL-18 gene promoter was performed in 161 patients with sarcoidosis and 176 healthy controls using the amplification refractory mutation system. Promoter activities were examined by a dual luciferase assay system in a cell line, THP-1. Results: There was no significant difference in the genotype distribution or allele frequency of all three SNPs between controls and patients with sarcoidosis. However, -607 C/A and -656 G/T were significantly associated with serum levels of IL-18 in patients with sarcoidosis, but not in controls. The promoter activity of the haplotype -137G/-607C/-656G, one of the most common haplotypes, was significantly higher than that of the other common haplotype, -137G/-607A/-656T, accounting for the association between serum IL-18 levels and the SNPs. Meanwhile, there was no strong association between the three SNPs and the clinical phenotypes, such as patient characteristics and clinical courses. Conclusions: Our results indicate that the differences in the promoter activity according to promoter haplotypes of the IL-18 gene result in an altered protein expression in sarcoidosis. However, it is unlikely that the three SNPs examined confer susceptibility to sarcoidosis.