EP3 Gene Polymorphisms in Japanese Patients With Stevens-Johnson Syndrome

Abstract

Purpose: : Stevens-Johnson syndrome (SJS) and the related disease, toxic epidermal necrolysis (TEN) are acute inflammatory disorders of the skin and mucous membranes including the ocular surface. Since we previously documented the association with several gene polymorphisms in Japanese SJS/TEN patients using single nucleotide polymorphism (SNP) association analysis of candidate genes, we have now performed a genome-wide association study (GWAS) of SJS/TEN to clarify the complete pathophysiology of SJS/TEN.

Methods: : SNP genotyping for the GWAS was performed with the commercially available GeneChip Human Mapping 500K Array Set (Affymetrix, Inc.) in 60 Japanese SJS/TEN patients with ocular surface complications and 300 Japanese healthy controls. In the EP3 gene region that is one of the candidate regions, SNPs were examined in more detail by using the iSelect^TM Custom Infinium Genotyping system (illumina, Inc.) in 75 patients and 448 controls. Six SNPs of the EP3 gene which showed significant associations (P<0.01) in the custom chip were sequenced in 100 patients and 160 controls to validate the results.

Results: : In the GWAS, several candidate regions associated with SJS/TEN were found. Some of those candidate regions included well-known gene regions, and the EP3 gene, one of the prostaglandin (PG) E receptor subtypes, was a representative gene. We particularly focused on EP3 gene polymorphisms and sequenced the 6 SNPs of the EP3 gene detected in the custom chip. All of the examined 6 SNPs were in Hardy-Weinberg equilibrium (p>0.001) and all of them showed a significant association with SJS/TEN. Furthermore, when we analyzed the association between these SNPs and non-steroidal anti-inflammatory drug (NSAID)-related SJS/TEN in 76 of the 100 patients, we found the same significant associations.

Conclusions: : Our results suggest that polymorphisms in the EP3 gene may be associated with SJS/TEN in the Japanese population. Since cold medicine including NSAIDs had induced SJS/TEN in 76% of our patients, and NSAIDs inhibit the production of PGE_2, the ligand of EP3, EP3 polymorphisms might be associated with NSAID-related SJS/TEN.

Keywords: genetics • conjunctivitis