Association between prostaglandin E receptor 3 polymorphisms and Stevens-Johnson syndrome identified by means of a genome-wide association study.
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.


OBJECTIVE
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.


CONCLUSIONS
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.
Ueta
Mayumi
M
Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Sotozono
Chie
C
Nakano
Masakazu
M
Taniguchi
Takazumi
T
Yagi
Tomohito
T
Tokuda
Yuichi
Y
Fuwa
Masahiro
M
Inatomi
Tsutomu
T
Yokoi
Norihiko
N
Tashiro
Kei
K
Kinoshita
Shigeru
S
D002460:Cell Line; D003228:Conjunctiva / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007249:Inflammation; D011110:Polymorphism, Genetic; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000819:agonists / Q000235:genetics*; D013262:Stevens-Johnson Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
D016207:Cytokines; C121546:ONO AE 248; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015232:Dinoprostone