2. Academic Validation
  3. OR11H1 Missense Variant Confers the Susceptibility to Vogt-Koyanagi-Harada Disease by Mediating Gadd45g Expression

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

  • Adv Sci (Weinh). 2024 Jan 2:e2306563. doi: 10.1002/advs.202306563.
Xingran Li 1,  Guoqing Wang 1,  Xiaotang Wang 1,  Wanqian Li 1,  Na Li 2,  Xianyang Liu 1,  Wei Fan 1,  Siyuan He 1,  Yue Han 3,  Guannan Su 1,  Qingfeng Cao 1,  Peizeng Yang 1,  Shengping Hou 1 4
Affiliations

Affiliations

  • 1 Chongqing Branch of National Clinical Research Center for Ocular Diseases; Chongqing Key Laboratory of Ophthalmology; Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400042, China.
  • 2 Department of Laboratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, 100005, China.
  • 3 Beijing Novogene Bioinformatics Technology Co.,Ltd, Beijing, 100600, China.
  • 4 Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
PMID: 38168905 DOI: 10.1002/advs.202306563
Abstract

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, Pcombined = 7.83 × 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-κB 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-κB pathways. Collectively, this study suggests that the OR11H1-A63 missense mutation may increase susceptibility to VKH disease in a GADD45G-dependent manner.

Keywords

GADD45G; OR11H1; RPE; Vogt-Koyanagi-Harada disease; uveitis; whole-exome sequencing.

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