Promoter polymorphisms in the IL-18 gene are associated with rheumatoid arthritis in two independent clinical cohorts

Introduction

IL-18 in synovial tissues of patients with rheumatoid arthritis (RA) promotes local inflammation via effects on innate and adaptive immune responses. Promoter polymorphisms may modulate IL-18 expression. Using two independent clinical cohorts, we determined the frequency of single nucleotide polymorphisms (SNPs) in the IL-18 promoter for RA patients.

Methods

DNA was extracted from peripheral blood mononuclear cells of 102 RA patients and 114 healthy donors in Frankfurt and from 153 RA patients and 187 healthy donors in Glasgow. In Frankfurt, DNA was amplified by polymerase chain reaction (PCR) and the presence of IL-18 SNP at positions -607 and -137 was determined by the restriction fragment length technique. Independently, in Glasgow, allele-specific PCR was performed for the same SNP sites.

Results

Frankfurt cohort: The -607 C and -137 G alleles were significantly more frequent in the RA population. Highly significant associations (P < 0.001) for RA were found for the homozygous C genotype in positions -607 and -137. Glasgow cohort: The -137 C allele was more frequent in RA patients (P < 0.01), but no effect was seen at position -607. Moreover, the -137CC genotype was more frequent in RA (P < 0.01). However in contrast to the Frankfurt dataset, no effect was seen at the -607 site.

Conclusion

SNPs at the -137 position in the IL-18 promoter appear to contribute to the genetic background in RA pathogenesis. Importantly, this has been independently identified in two clinical cohorts, by the use of distinct methodologies, in Germany and the UK. IL-18 is a promising therapeutic target and, as such defining factors that modulate its regulation in rheumatoid tissues is important.