Association between prostaglandin E receptor 3 polymorphisms and Stevens-Johnson syndrome identified by means of a genome-wide association study
Association between prostaglandin E receptor 3 polymorphisms and Stevens-Johnson syndrome identified by means of a genome-wide association study
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DOI：
10.1016/j.jaci.2010.08.007
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发表时间：
2010-12-01
影响因子：
14.2
通讯作者：
Kinoshita, Shigeru
中科院分区：
文献类型：
--
作者：
Ueta, Mayumi;Sotozono, Chie;Kinoshita, Shigeru
背景资料：Stevens-Johnson综合征（SJS）及其严重变体中毒性表皮坏死松解症（TEN）是皮肤和粘膜的急性炎性大疱性反应。他们往往会影响眼表，并可能导致永久性视力dysfunctions.Objectives：我们试图发现遗传标记SJS/TEN susceptibility.Methods：我们进行了全基因组关联研究与60例患者和300名对照组。我们应用严格的过滤和视觉评估来选择单核苷酸多态性（SNP）和高错误发现率阈值。我们对发现候选SNP的区域进行了精细定位，并通过测序确认了结果。我们评估了激动剂激活的前列腺素E受体3（EP 3）的功能，该基因含有几个SNP，在调节人结膜上皮（CE）细胞中细胞因子的产生。结果：我们发现了3个通过错误发现率阈值的SNPs。1个（rs 17131450）与EP 3基因相近。因此，我们详细分析了EP 3区域并鉴定了5个其他SNP。我们证实了SJS/TEN与所有6个SNP之间的关联。激活的EP 3在对照CE细胞中表达，并且它抑制polyI：C刺激的细胞因子产生，表明EP 3可能有助于预防眼表面炎症。一致的是，EP 3水平在CE细胞的患者比在对照subjects.Conclusion：我们证明，使用遗传和功能分析，EP 3可能是一个关键的球员在发病机制SJS/TEN伴随眼部并发症。（J Allergy Clin Immunol 2010;126：1218-25.）
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. (J Allergy Clin Immunol 2010;126:1218-25.)