To the Editor
Sánchez, et al have recently reported an association between a putative functional genetic variant in the promoter region of IL18 (rs360719) and systemic lupus erythematosus in Spanish patients1. They found an increase in the relative expression of IL18 mRNA in individuals with the rs360719 lupus-risk allele1. Interleukin 18 (IL-18) is a pleiotropic cytokine that can induce Th1 and Th2 responses in the presence and absence, respectively, of IL-122. Studies have described overproduction of IL-18 in several autoimmune and inflammatory diseases including Behçet’s disease (BD) and lupus3,4. Indeed, serum IL-18 levels in patients with lupus and BD correlate with disease activity5,6.
We attempted to replicate the results of Sánchez, et al in a set of Turkish patients with lupus. We examined if the same putative functional IL18 polymorphism is associated with BD in Turkish patients. We genotyped 2 additional potentially functional single-nucleotide polymorphisms (SNP) in the IL18 promoter region (rs1946518, −607 C/A, and rs187238, −37 G/C). Our sample set consisted of 189 patients with lupus, 156 with BD, and 253 ethnically matched healthy controls.
All lupus patients and all BD patients fulfilled the 1997 American College of Rheumatology classification criteria for lupus7 and the 1990 International Study Group classification criteria for BD8, respectively. Genotyping was performed using TaqMan allelic discrimination assays (Applied Biosystems, Foster City, CA, USA). The genotyping success rate was ≥ 97.5%. Only individuals successfully genotyped in at least 2 out of the 3 SNP were included in the analysis. There was no departure from Hardy-Weinberg equilibrium in controls. Data analysis was performed using PLINK and Haploview 4.2.
We found no genetic association between IL18 and lupus in Turkish patients (Table 1). The frequency of the minor allele in rs360719 was 19.3% in cases and 19.5% in controls (OR 0.99, 95% CI 0.70–1.40, p = 0.95). This is in contrast to the findings of Sánchez, et al, suggesting that the genetic association with IL18 might be limited to specific ethnicities. Our study had 91% power to detect a genetic association in rs360719 with the previously reported odds ratio of 1.53 (assuming a dominant model, disease prevalence = 0.001, α= 0.05). More recent work using a large set of lupus patients and controls also failed to demonstrate a genetic association between IL18 and lupus9.
Table 1.
Genetic association analysis of single-nucleotide polymorphisms located in the promoter region of IL18 in lupus cases and controls.
| Frequency | |||||||
|---|---|---|---|---|---|---|---|
| Marker | Position | Minor Allele | Cases, n (%) | Controls, n (%) | OR | (95% CI) | p |
| rs187238 | −137 | C | 70 (19.4) | 98 (20.2) | 0.96 | (0.68–1.35) | 0.80 |
| rs1946518 | −607 | A | 141 (39.2) | 172 (35.8) | 1.15 | (0.87–1.53) | 0.32 |
| rs360719 | −1297 | C | 69 (19.3) | 93 (19.5) | 0.99 | (0.70–1.40) | 0.95 |
We found a genetic association between allele “A” in rs1946518 (–607 C/A) and BD (OR 1.48, 95% CI 1.10–1.97, p = 0.0088). Our data indicate that allele “A” is the minor allele in rs1946518 in Turkish individuals, consistent with the European-derived CEU samples in HapMap. This is contrary to the findings of Keskin, et al, who reported that allele “C” is the minor allele and BD-associated allele in rs1946518 from studies in an independent Turkish sample10. A genetic association of rs1946518 albeit with allele “C” was also reported in Korean patients with BD11. This association was not found in another independent Korean sample set12. Of note, our study had 85% power to detect a genetic association in rs1946518 (assuming a dominant model, disease prevalence = 0.001, α= 0.05). We detected no genetic association with rs360719 or rs187238 in BD (Table 2). However, our study was underpowered to detect an association in these 2 SNP given the minor allele frequencies and odds ratios detected.
Table 2.
Genetic association analysis of single-nucleotide polymorphisms located in the promoter region of IL18 in Behçet’s disease cases and controls.
| Frequency | |||||||
|---|---|---|---|---|---|---|---|
| Marker | Position | Minor Allele | Cases, n (%) | Controls, n (%) | OR | (95% CI) | p |
| rs187238 | −137 | C | 68 (22.2) | 98 (20.2) | 1.13 | (0.80–1.60) | 0.49 |
| rs1946518 | −607 | A | 140 (45.2) | 172 (35.8) | 1.48 | (1.10–1.97) | 0.0088 |
| rs360719 | −1297 | C | 66 (22.0) | 93 (19.5) | 1.17 | (0.82–1.67) | 0.39 |
We found a genetic association between IL18 and BD but not lupus in Turkish patients. Palomino-Morales, et al have reported a similar association between allele “A” in rs1946518 and giant cell arteritis13. In addition, the association between rs187238 and Henoch-Schönlein purpura has been reported14. This suggests that IL18 might be a common susceptibility locus for at least 3 vasculitic diseases. Whether IL18 is a susceptibility gene in other vasculitides remains to be investigated.
Acknowledgments
Supported by the Fleming Scholarship Program at the Oklahoma Medical Research Foundation (J. Htoon); and National Institutes of Health (NIH) grant R03AI076729 from the National Institute of Allergy and Infectious Diseases, NIH grants P20RR020143 and P30AR053483; and funding from the American College of Rheumatology Research and Education Foundation Rheumatology Investigator Award (Dr. Sawalha). The authors thank Dr. Elena Sanchez for her insightful suggestions.
Contributor Information
JASMINE HTOON, Oklahoma Medical Research Foundation.
AJAY NADIG, Oklahoma Medical Research Foundation.
TRAVIS HUGHES, Oklahoma Medical Research Foundation.
SULE YAVUZ, Department of Rheumatology, Marmara University, School of Medicine, Istanbul, Turkey.
HANER DIRESKENELI, Department of Rheumatology, Marmara University, School of Medicine, Istanbul, Turkey.
GÜHER SARUHAN-DIRESKENELI, Department of Physiology, Istanbul University, Istanbul School of Medicine, Istanbul, Turkey.
AMR H. SAWALHA, Oklahoma Medical Research Foundation; Department of Medicine, University of Oklahoma Health Sciences Center; US Department of Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA.
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