Vogt-Koyanagi-Harada (VKH) disease is a severe autoimmune disease. Herein, whole-exome sequencing (WES) study are performed on 2,573 controls and 229 VKH patients with follow-up next-generation sequencing (NGS) in a collection of 2,380 controls and 2,278 VKH patients. A rare c.188T>C (p Val63Ala) variant in the olfactory receptor 11H1 (OR11H1) gene is found to be significantly associated with VKH disease (rs71235604, P-combined = 7.83 x 10(-30), odds ratio = 3.12). Functional study showes that OR11H1-A63 significantly increased inflammatory factors production and exacerbated barrier function damage. Further studies using RNA-sequencing find that OR11H1-A63 markedly increased growth arrest and DNA-damage-inducible gamma (GADD45G) expression. Moreover, OR11H1-A63 activates the MAPK and NF-kappa B pathways, and accelerates inflammatory cascades. In addition, inhibiting GADD45G alleviates inflammatory factor secretion, likely due to the regulatory effect of GADD45G on the MAPK and NF-kappa B pathways. Collectively, this study suggests that the OR11H1-A63 missense mutation may increase susceptibility to VKH disease in a GADD45G-dependent manner.
基金:
National Natural Science Foundation Project of China; National Key Clinical Specialties Construction Program of China, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing Key Laboratory of Ophthalmology (CSTC) [2008CA5003]; Program for Youth Innovation in Future Medicine, Chongqing Medical University [W0047]; [82070951]; [82271078]; [82371045]
第一作者机构:[1]Chongqing Med Univ, Chongqing Eye Inst, Chongqing Branch Natl Clin Res Ctr Ocular Dis, Chongqing Key Lab Ophthalmol,Affiliated Hosp 1, Chongqing 400042, Peoples R China
共同第一作者:
通讯作者:
通讯机构:[1]Chongqing Med Univ, Chongqing Eye Inst, Chongqing Branch Natl Clin Res Ctr Ocular Dis, Chongqing Key Lab Ophthalmol,Affiliated Hosp 1, Chongqing 400042, Peoples R China[4]Capital Med Univ, Beijing Tongren Eye Ctr, Beijing Key Lab Ophthalmol & Visual Sci, Beijing Inst Ophthalmol,Beijing Tongren Hosp, Beijing 100730, Peoples R China
推荐引用方式(GB/T 7714):
Li Xingran,Wang Guoqing,Wang Xiaotang,et al.OR11H1 Missense Variant Confers the Susceptibility to Vogt-Koyanagi-Harada Disease by Mediating Gadd45g Expression[J].ADVANCED SCIENCE.2024,11(11):doi:10.1002/advs.202306563.
APA:
Li, Xingran,Wang, Guoqing,Wang, Xiaotang,Li, Wanqian,Li, Na...&Hou, Shengping.(2024).OR11H1 Missense Variant Confers the Susceptibility to Vogt-Koyanagi-Harada Disease by Mediating Gadd45g Expression.ADVANCED SCIENCE,11,(11)
MLA:
Li, Xingran,et al."OR11H1 Missense Variant Confers the Susceptibility to Vogt-Koyanagi-Harada Disease by Mediating Gadd45g Expression".ADVANCED SCIENCE 11..11(2024)