Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea

Zhili Deng, Mengting Chen, Zhixiang Zhao, Wenqin Xiao, Tangxiele Liu, Qinqin Peng, Zheng Wu, San Xu, Wei Shi, Dan Jian, Ben Wang, Fangfen Liu, Yan Tang, Yingxue Huang, Yiya Zhang, Qian Wang, Lunquan Sun, Hongfu Xie, Guohong Zhang () and Ji Li ()
Additional contact information
Zhili Deng: Central South University
Mengting Chen: Central South University
Zhixiang Zhao: Central South University
Wenqin Xiao: Central South University
Tangxiele Liu: Central South University
Qinqin Peng: Central South University
Zheng Wu: Central South University
San Xu: Central South University
Wei Shi: Central South University
Dan Jian: Central South University
Ben Wang: Central South University
Fangfen Liu: Central South University
Yan Tang: Central South University
Yingxue Huang: Central South University
Yiya Zhang: Central South University
Qian Wang: Hunan Binsis Biotechnology Co., Ltd
Lunquan Sun: Xiangya Hospital, Central South University
Hongfu Xie: Central South University
Guohong Zhang: Shantou University Medical College
Ji Li: Central South University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Rosacea is a chronic inflammatory skin disorder with high incidence rate. Although genetic predisposition to rosacea is suggested by existing evidence, the genetic basis remains largely unknown. Here we present the integrated results of whole genome sequencing (WGS) in 3 large rosacea families and whole exome sequencing (WES) in 49 additional validation families. We identify single rare deleterious variants of LRRC4, SH3PXD2A and SLC26A8 in large families, respectively. The relevance of SH3PXD2A, SLC26A8 and LRR family genes in rosacea predisposition is underscored by presence of additional variants in independent families. Gene ontology analysis suggests that these genes encode proteins taking part in neural synaptic processes and cell adhesion. In vitro functional analysis shows that mutations in LRRC4, SH3PXD2A and SLC26A8 induce the production of vasoactive neuropeptides in human neural cells. In a mouse model recapitulating a recurrent Lrrc4 mutation from human patients, we find rosacea-like skin inflammation, underpinned by excessive vasoactive intestinal peptide (VIP) release by peripheral neurons. These findings strongly support familial inheritance and neurogenic inflammation in rosacea development and provide mechanistic insight into the etiopathogenesis of the condition.

Date: 2023
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DOI: 10.1038/s41467-023-39761-2

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