Association between prostaglandin E receptor 3 polymorphisms and Stevens-Johnson syndrome identified by means of a genome-wide association study - 07/08/11
, Chie Sotozono, MD, PhD a, , Masakazu Nakano, PhD b, Takazumi Taniguchi, PhD b, Tomohito Yagi, MD, PhD b, Yuichi Tokuda b, Masahiro Fuwa b, Tsutomu Inatomi, MD, PhD a, Norihiko Yokoi, MD, PhD a, Kei Tashiro, MD, PhD b, Shigeru Kinoshita, MD, PhD a, ⁎ 
Reprint requests: Shigeru Kinoshita, MD, PhD, Department of Ophthalmology, Kyoto Prefectural University of Medicine, Hirokoji, Kawaramachi, Kamigyoku, Kyoto 602-0841, Japan.Abstract |
Background |
Stevens-Johnson syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), are acute inflammatory vesiculobullous reactions of the skin and mucosa. They often affect the ocular surface and can result in permanent visual dysfunction.
Objectives |
We sought to discover genetic markers for SJS/TEN susceptibility.
Methods |
We performed a genome-wide association study with 60 patients and 300 control subjects. We applied stringent filter and visual assessments for selecting single nucleotide polymorphisms (SNPs) and a high false discovery rate threshold. We fine-mapped the region where a candidate SNP was found and confirmed the results by means of sequencing. We evaluated the function of agonist-activated prostaglandin E receptor 3 (EP3), the gene for which contained several SNPs, in regulating cytokine production in human conjunctival epithelial (CE) cells. The expression levels of EP3 in the CE cells from patients and control subjects were also compared.
Results |
We identified 3 SNPs that passed the false discovery rate threshold. One (rs17131450) was close to the EP3 gene. Therefore we analyzed the EP3 region in detail and identified 5 other SNPs. We confirmed the association between SJS/TEN and all 6 SNPs. Activated EP3 was expressed in control CE cells, and it suppressed polyI:C-stimulated cytokine production, suggesting that EP3 might help prevent ocular surface inflammation. Concordantly, the EP3 levels were much lower in the CE cells of the patients than in those of the control subjects.
Conclusion |
We demonstrated, using both genetic and functional analyses, that EP3 could be a key player in the pathogenesis of SJS/TEN accompanied by ocular complications.
Le texte complet de cet article est disponible en PDF.Key words : Prostaglandin E receptor 3, Stevens-Johnson syndrome, toxic epidermal necrolysis, genome-wide association study, single nucleotide polymorphism
Abbreviations used : BRLMM, CE, EP3, FDR, GAPDH, GWAS, HapMap-CHB, HapMap-JPT, LD, MAF, NSAID, PGE2, PHCjE, QC, SJS, SNP, TEN, TLR3
Plan
| Supported in part by grants-in-aid for scientific research from the Japanese Ministry of Health, Labour and Welfare; the Japanese Ministry of Education, Culture, Sports, Science and Technology; a research grant from the Kyoto Foundation for the Promotion of Medical Science; and the Intramural Research Fund of Kyoto Prefectural University of Medicine. |
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| Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. |
Vol 126 - N° 6
P. 1218 - décembre 2010 Retour au numéro
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