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

Interleukin (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.

Genotyping of three SNPs, -137 G/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.

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.

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.