Differential haplotypic expression of the interleukin-18 gene

Abstract

Interleukin 18 (IL-18) is suspected to play an important role in atherosclerosis and plaque vulnerability. We had previously shown that haplotypes combining two IL18 gene polymorphisms in complete linkage disequilibrium, C-105T (rs360717) in 5 0 -untranslated region (UTR) and A þ 183G (rs5744292) in 3 0 -UTR, were related to IL-18 circulating levels and cardiovascular outcome, the C À105 G þ 183 haplotype being associated with lower IL-18 levels and lower cardiovascular risk. This study was aimed at investigating the functional role of the two polymorphisms and their haplotypes on IL18 expression levels. Allelic imbalance experiments conducted in 24 and 20 subjects heterozygous for the C-105T and the A þ 183G polymorphisms did not detect any difference when subjects were considered as a whole (À0.00970.044, P ¼ 0.85 and þ 0.11470.082, P ¼ 0.18, respectively). However, when splitting individuals according to their haplo-genotype, the haplotype C À105 G þ 183 was associated with a lower expression level than C À105 A þ 183 (À0.28770.076, P ¼ 0.005), but did not differ from T À105 A þ 183 (À0.13870.083, P ¼ 0.13). The lower expression associated with C À105 G þ 183 was confirmed by real-time reverse transcription-PCR. Transfection of different haplotypic versions of the 3 0 -UTR did not show any difference in the expression of an upstream reporter gene. A 10-h study of the mRNA degradation kinetics by allelic imbalance with the A þ 183G polymorphism did not show any differential allelic degradation. In conclusion, the haplotype associated with lower IL-18 circulating concentrations and a lower cardiovascular risk was consistently associated with decreased IL18 expression levels, although the exact functional mechanisms remain to be elucidated.

A Functional SNP of the Interleukin-18 Gene Is Associated with the Presence of Hepatocellular Carcinoma in Hepatitis B Virus-Infected Patients

“…Cloning and gene expression analysis have shown that two IL-18 gene promoter SNPs at positions -607 and -137 could cause differences in transcription factor binding and have an impact on IL-18 gene activity, as well as a potential effect on IFN-c [26]. A recent report showed that haplotypes associated with lower IL-18 circulating concentrations were consistently associated with decreased levels of expression of IL-18 [27].…”

Analysis of interleukin-18 promoter polymorphisms and changes in interleukin-18 serum levels underscores the involvement of interleukin-18 in recurrent spontaneous miscarriage

“…IL-18 is expressed by epithelial cells of the amnion, chorionic cells, and decidual cells but not by syncytiotrophoblasts of the villi, and altered IL-18 levels have been linked to increased RSM risk (10)(11)(12)21). Insofar as IL-18 promoter singlenucleotide polymorphisms (SNPs) are associated with differential expression of IL-18 (22), this suggests a genetic susceptibility of RSM based on IL-18 promoter variants or haplotypes. In this study, we evaluated rs1946519 (À656C/A), rs187238 (À137G/C), rs360718 (À119A/C), and rs360717 (À105G/A) IL-18 promoter SNPs by allelic discrimination (real-time polymerase chain reaction) in women with RSM and controls and identified specific 4-locus haplotypes associated with increased risk of RSM.…”

Interleukin-18 promoter polymorphisms in Japanese patients with rheumatoid arthritis: protective effect of the T allele and T/T genotype at rs360722

“…Within the entire region of the IL-18 gene, neither nonsynonymous SNPs nor ones that may interfere with mRNA splicing have been discovered. By using a haplotypic approach in several cohort studies, however, global associations between IL-18 haplotypes and plasma IL-18 levels were observed [39,40], although haplotypes explained only 1.8% of the variability of IL-18 levels [41]. As for the A-T-T haplotype, unfortunately, there have been no studies investigating the direct association between the haplotype and IL-18 protein levels.…”