OR11H1 Missense Variant Confers the Susceptibility to Vogt-Koyanagi-Harada Disease by Mediating Gadd45g Expression

作者全名："Li, Xingran; Wang, Guoqing; Wang, Xiaotang; Li, Wanqian; Li, Na; Liu, Xianyang; Fan, Wei; He, Siyuan; Han, Yue; Su, Guannan; Cao, Qingfeng; Yang, Peizeng; Hou, Shengping"

作者地址："[Li, Xingran; Wang, Guoqing; Wang, Xiaotang; Li, Wanqian; Liu, Xianyang; Fan, Wei; He, Siyuan; Su, Guannan; Cao, Qingfeng; Yang, Peizeng; Hou, Shengping] 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; [Li, Na] Capital Med Univ, Beijing Tongren Hosp, Dept Lab Med, Beijing 100005, Peoples R China; [Han, Yue] Beijing Novogene Bioinformat Technol Co Ltd, Beijing 100600, Peoples R China; [Hou, Shengping] Capital Med Univ, Beijing Tongren Eye Ctr, Beijing Key Lab Ophthalmol & Visual Sci, Beijing Inst Ophthalmol,Beijing Tongren Hosp, Beijing 100730, Peoples R China"

通信作者："Yang, PZ; Hou, SP (通讯作者)，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.; Hou, SP (通讯作者)，Capital Med Univ, Beijing Tongren Eye Ctr, Beijing Key Lab Ophthalmol & Visual Sci, Beijing Inst Ophthalmol,Beijing Tongren Hosp, Beijing 100730, Peoples R China."

来源：ADVANCED SCIENCE

ESI学科分类：PHYSICS

WOS号：WOS:001134933900001

JCR分区：Q1

影响因子：15.1

年份：2024

卷号：11

期号：11

开始页：　

结束页：　

文献类型：Article

关键词：GADD45G; RPE; uveitis; Vogt-Koyanagi-Harada disease; whole-exome sequencing

摘要："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."

基金机构："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]"

基金资助正文："This study was supported by the National Natural Science Foundation Project of China (82070951, 82271078, 82371045), the 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) and Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0047)."