Association between adult-onset Still's disease and interleukin-18 gene polymorphisms

Abstract

Recently, we reported that serum concentration of IL-18 is strikingly high in patients with adult-onset Still's disease (AOSD). The aim of the present study was to screen for genetic polymorphisms in the human IL-18 (hIL-18) gene and to determine the association of polymorphisms with susceptibility to AOSD. We investigated the 6.7 kb region upstream of exon 2 of hIL-18 gene, in which a promoter activity had been reported. Sixteen AOSD patients, 144 rheumatoid arthritis (RA) patients and 92 healthy control individuals were studied. We found seven single nucleotide polymorphisms and a single 9 bp insertion which were frequently present in the AOSD patients. Three haplotypes including a unique combination of these polymorphisms were also determined. Of them, haplotype S01 contained all eight of these polymorphisms. The frequency of individuals carrying a diplotype configuration, ie a combination of two haplotypes, of S01/S01 was significantly higher in the AOSD patients than in the healthy controls (P ¼ 0.00059, Fischer's exact probability test, odds ratio [OR] ¼ 7.81, 95% confidence interval [95% CI] ¼ 2. 48-24.65) and the RA patients (P ¼ 0.015, Fischer's exact probability test, OR ¼ 4.0, 95% CI ¼ 1.39-11.54). We therefore conclude that possession of the diplotype configuration of S01/S01 is a major genetic risk factor for susceptibility to AOSD.

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

“…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 SNP in À137 was in contrast described in another Asian population, but showed no impact on the occurrence of RA.…”

“…20 The À137C/G polymorphism, however, was not detected in this cohort. 20 SNP in À137 was in contrast described in another Asian population, but showed no impact on the occurrence of RA. 22 Although these data of various case-control studies are not absolutely conclusive and require some further confirmation in independent cohorts and populations, the overall impression is still indicative of a functional importance for IL-18 promoter polymorphisms for the development of autoimmune diseases.…”

“…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.…”

“…Different variations in We have chosen to report the positions À607 (rs187238) and À137 (rs1946518), 24 which are identical to positions À640 and À170 defined in another publication. 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][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.…”