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Association of Interleukin 18 Polymorphisms with Adult Onset Still's Disease in Korea

To the Editor:

Adult onset Still's disease (AOSD) is a multisystemic inflammatory disorder of unknown origin. The pathogenesis of AOSD is associated with elevated levels of serum cytokines such as interleukin 1 (IL-1), tumor necrosis factor-a (TNF-a), IL-6, IL-18, and interferon-g¹ (IFN-g). A recent study showed that levels of serum IL-18 in patients with active AOSD were very high and were correlated with the disease severity and activity². IL-18 is a new member of the IL-1 family, and it is a potent inducer of IFN-g from T cells and natural killer cells, promoting a Th-1-type immune response through the activation of nuclear factor-kB³. In Japanese studies, IL-18 single-nucleotide polymorphisms (SNP) in the promoter region have been associated with juvenile idiopathic arthritis (JIA)⁴ and AOSD⁵. We hypothesized that SNP of the IL-18 gene might be associated with AOSD in Koreans.

We genotyped 4 SNP of the IL-18 gene, denoted –656G/T, –607C/A, –137G/C, and 1248A/G, in 79 patients with AOSD and 130 healthy Korean individuals. All AOSD patients satisfied the criteria of Yamaguchi, et al⁶. Written informed consent was obtained from all participants before enrollment.

Patients were subdivided into groups according to disease course: monocyclic systemic, polycyclic systemic, or chronic articular type⁷. Genotyping was performed using the sequence-specific polymerase chain reaction method. Allelic, genotypic, and haplotypic associations were analyzed by chi-square test. The frequencies of the haplotype and linkage disequilibrium were estimated using the Arlequin program (available from: http://anthro.unige.ch/software/arlequin/about.php).

No differences in genotypic frequencies were found between patients and the controls. The A allele at position –607 was more frequent in AOSD patients than in controls (OR 1.510, 95% CI 1.01–2.25, p = 0.042; Table 1). The AA genotype at position –607 was more frequent in patients with the monocyclic systemic type disease than in controls (OR 3.538, 95% CI 1.17–10.70, p = 0.031; Table 2).

Table 1. Allelic and genotypic frequencies of IL-18 gene polymorphisms in Korean patients with AOSD and controls.

Table 2. Genotypic frequencies of IL-18 single-nucleotide polymorphisms by disease course. The patients who had disease duration less than 1 year were excluded from the analysis of disease course. Monocyclic systemic type: only one episode of systemic manifestation, followed by a complete remission within 1 year after disease onset; polycyclic systemic type: > 1 episode of systemic manifestation, followed by partial or complete remission within 1 year after disease onset or subsequent attack; chronic articular type: persistent arthritis involving at least one joint area and lasting more than 6 months.

SNP at positions –137 and –607 have been suggested to have an influence on IL-18 gene activity, as both SNP alter the transcription factor binding site. In the previous study, patients homozygous for C at position –607 and G at position –137 had increased promoter activity and higher levels of IL-18 mRNA expression compared to other genotypes⁸. We found that the A allele was associated with AOSD patients, and the AA genotype at position –607 specifically with the monocyclic systemic disease type. When we excluded the monocyclic systemic type, there was no difference between the AOSD patients and controls in the allelic and genotypic frequencies at position –607. Sugiura, et al^4,5 showed that 12 SNP within the promoter region of the IL-18 gene were associated with susceptibility to JIA in Japanese patients. There was a strong association between the diplotype configuration of S01/S01 of the IL-18 gene and JIA as well as AOSD. T at position –656, A at position –607, and G at position –137 were the components of haplotype S01. The diplotype configuration of S01/S01 was linked to significantly higher serum levels of IL-18 in systemic JIA. In addition, the serum level of IL-18 was reported to be higher in patients with the monocyclic systemic disease than in those with the chronic articular type⁷. These data suggest that the A allele in –607 may be associated with higher levels of serum IL-18, and with the monocyclic systemic disease rather than the other subtypes. When we reconstructed the 4 main haplotypes in this study -- GCGA, TAGA, TACG, and TCGA -- we found no differences in haplotype frequencies between patients and controls, but there was strong linkage disequilibrium in all 4 SNP (all D > 0.6, p < 0.0001). Also, the frequency of the TAGA/TAGA diplotype configuration was not different between the AOSD patients and the controls (OR 2.149, 95% CI 0.882–5.238, p = 0.087). When we measured the IL-18 concentrations from culture supernatants of mononuclear cells in the presence of PMA-ionomycin, the mean IL-18 level in the controls carrying the TAGA/TAGA diplotype did not differ from that in controls carrying the GCGA/GCGA diplotype (data not shown).

It seemed that high levels of production of IL-18 might not be directly associated with the IL-18 gene polymorphisms tested in this study. The possible reasons for the inconsistency compared to other studies are unclear. One possible explanation for the discrepancy would be strong linkage disequilibrium in the 4 SNP of the IL-18 promoter region. We should consider that there might be other unknown functional mutations elsewhere in the IL-18 sequence, and also in the other independent genes affecting the secretion of IL-18. Another explanation might be the variation of genetic susceptibility between ethnic groups⁹. Allelic heterogeneity exists between ethnic groups, and different variations within the same gene should contribute to disease risk¹⁰.

Our study was on a relatively large scale considering the rarity of AOSD. We showed that the A allele at position –607 in the IL-18 promoter region may be associated with the development of AOSD, especially in the monocyclic systemic subgroup.

JIN-HYUN WOO, MD, Instructor; SANG-SEOKG SEONG, MD, Instructor; DAE-HYUN YOO, MD, PhD, Professor of Medicine, Division of Rheumatology, Department of Internal Medicine, The Hospital for Rheumatic Diseases, Hanyang University College of Medicine, Seoul, Korea. Address reprint requests to Dr. Yoo; E-mail: dhyoo@hanyang.ac.kr

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