Association of interleukin-18 promoter polymorphisms with WHO pathological classes and serum IL-18 levels in Chinese patients with lupus nephritis

Abstract

Accumulating evidence indicates that interleukin (IL)-18 has a central role in the pathogenesis of lupus nephritis (LN). Although two recent studies showed that IL-18 promoter gene polymorphisms might be associated with systemic lupus erythematosus (SLE), to our knowledge, there have not been any reports concerning their association with LN. The aim of our study was to investigate the association of IL-18 promoter polymorphisms with World Health Organization pathological classes and identify their functional correlations. Sequence-specific primer polymerase chain reaction and the restriction fragment length polymorphism method were used to analyse the genotypes of IL-18 promoter polymorphism at the position -607 in 101 unrelated patients with LN, 64 non-renal patients with SLE and 174 ethnically matched healthy controls. Serum IL-18 levels were determined using enzyme-linked immunosorbent assay during the active phase. Immunohistochemical analysis was performed for IL-18 expression on renal biopsies from 72 patients with LN. Our results showed that patients with non-renal SLE had significantly higher frequencies of SNP-607/AA when compared to patients with LN (37.5% vs 18.8%, P < 0.05). LN patients with the AA genotype had significantly lower levels of serum IL-18 than those with the CA or CC genotype (P < 0.01) and also had lower levels of glomerular IL-18 expression than those with the CC genotype (P < 0.05). Significantly, higher frequencies of the SNP-607/AA genotype were observed in LN patients with WHO class III than in those with class IV (34.6% vs 15.6%, P < 0.05). The SNP-607/AA genotype was not observed in patients with LN who progressed to end-stage renal failure that required haemodialysis or renal transplantation. In conclusion, the SNP-607/AA genotype that had lower IL-18 levels might be a genetically protective factor against renal involvement in Chinese patients with SLE and against development of severe nephritis in patients with LN.

Functional Association of Interleukin 18 Gene −607 (C/A) Promoter Polymorphisms with Disease Course in Chinese Patients with Adult-onset Still’s Disease

“…Our data were consistent with recent results that showed lupus patients with AA genotype had significantly lower IL-18 levels than those with the CC and CA genotypes 29,31 . Comparison of promoter polymorphisms of IL-18 gene with sequences in the TRANSFAC (Gene Transcription Factor) database suggest that the change from C to A at position -607 possibly disrupts a potential CREBP binding site and may reduce IL-18 production 23 .…”

Elevated interleukin-18 and skewed Th1:Th2 immune response in lupus nephritis

“…LPS and TNF did not increase IL-18 mRNA levels while the production of proIL-18 and, especially, mature IL-18 was markedly enhanced in response to stimulation, suggesting that posttranscriptional processing was responsible for the up-regulation of renal IL-18 during the progression of lupus nephritis [15]. Latest two studies showed that promoter polymorphism inXuenced expression of IL-18 [20,21]. Moreover, one latest Spanish study conWrmed an important role of the novel IL18 rs360719 variant in determining the susceptibility to SLE [22].…”

The associations of IL-18 serum levels and promoter polymorphism with tacrolimus pharmacokinetics and hepatic allograft dysfunction in Chinese liver transplantation recipients

“…Two single nucleotide polymorphisms (A-607C and G-137C) in the promoter region of the IL-18 gene have been found repeatedly to be associated with the IL-18 promoter transcription activity (Khripko et al, 2008;Chen et al, 2009). We attempted to elucidate the inherited basis of the differences among individual responses to the drugs association with cytokine genetic background, so as to identify the right dose of tacrolimus for each recipient.…”