Interleukin-18 Promoter Polymorphisms in Type 1 Diabetes

Abstract

Type 1 diabetes is believed to be a Th1 lymphocyte-mediated disease, and both environmental and genetic factors play a role in its pathogenesis. It was recently found that interleukin (IL)-18 acts as a proinflammatory cytokine and, in synergy with IL-12, promotes development of Th1 lymphocyte response by induction of gamma-interferon production. The aim of our study was to evaluate the frequency of known polymorphisms in the IL-18 promoter in patients with type 1 diabetes in comparison with healthy control subjects, since higher levels of IL-18 were recently reported in the subclinical stage of type 1 diabetes. We studied two recently described single-nucleotide polymorphisms of the promoter of IL-18 gene at the position -137 and -607, which have been suggested to cause differences in transcription factor binding and have an impact on IL-18 gene activity. The genotype distribution differed significantly between patients with type 1 diabetes and control subjects. The difference reflected an increase in the GC genotypes and a decrease in GG genotypes at position -137 in the promoter of IL-18 gene. AA genotype at position -607 was found only in the control group. The results also demonstrated that the contribution of -137GC genotypes to genetic susceptibility to type 1 diabetes differs depending on the combination of IL-18 promotor gene haplotypes. Our study suggests the first evidence of an association between type 1 diabetes and polymorphisms in the promoter of IL-18 gene.

Disease association of two distinct interleukin-18 promoter polymorphisms in Caucasian rheumatoid arthritis patients

“…A protective effect of the À607AA diplotype was recently postulated in a case-control study of Asian RA patients, and an influence of IL-18 promoter polymorphisms on the occurrence of different inflammatory and autoimmune diseases was also suggested by several other casecontrol studies. [20][21][22][23] Our data of two separate Caucasian cohorts from Germany and Scotland showed divergent disease associations on the single-locus diplotype level, which need to be interpreted with caution in respect of the HW disequilibria observed in the respective RA cohorts. Moreover, the analyses of the compound data set were complicated by departure from HWE also in healthy controls, which was on a first glance suggestive for typing errors.…”

“…This suspicion appears as far as possible excluded by use of two independent techniques in many subjects, which gave absolutely identical results, and also by the successful use of the same method in other studies. [21][22][23][24][25] Among more theoretical explanations as genetic selection, a stratification effect by composing our two independent cohorts has to be considered here. Departure from HWE, however, required a more conservative statistical calculation of allele and diplotype associations by trend tests, which, in contrast to the exact genotype w 2 tests, failed statistical significance for both single loci.…”

“…20 Recent studies in a Polish cohort showed an important contribution of À137C and À137CC to the genetic risk in type I diabetes, and possibly a protective effect of À607AA. 21 In a Japanese study, a distinct genotype of À607A in combination with six other SNPs and a 9 bp insertion upstream from À607 was reported to be strongly associated with adult onset Still's disease (AOSD), and also to a lesser degree with RA. 20 The À137C/G polymorphism, however, was not detected in this cohort.…”

“…[20][21][22][23] The IL-18 promoter and IL-18 gene represent attractive candidate regions for gene polymorphism analyses in RA given its functional role in synovitis. Therefore, we have utilized two independent cohorts of Caucasian RA patients and healthy donors (HD) for polymorphism association analysis.…”

Essential pathogenic role of endogenous IL‐18 in murine diabetes induced by multiple low doses of streptozotocin. Prevention of hyperglycemia and insulitis by a recombinant IL‐18‐binding protein: Fc construct

“…This view concurs both with studies conducted in NOD mice, where IL-18 transcripts can be detected in the early phases of the insulitis process induced by cyclophosphamide [16], and in humans, where increased blood levels of IL-18 are observed in individuals at high risk of developing type 1 DM but not in newly diagnosed or in long-lasting type 1 DM patients [17]. In addition, evidence has been provided for an association between type 1 diabetes and polymorphism in the promoter of the IL-18 gene [18].…”