Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea.
Zhi-Li DengMengting ChenZhixiang ZhaoWenqin XiaoTangxiele LiuQinqin PengZheng WuSan XuWei ShiDan JianBen WangFangfen LiuYan TangYingxue HuangYiya ZhangQian WangLun-Quan SunHongfu XieGuohong ZhangJi LiPublished in: Nature communications (2023)
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.
Keyphrases
- genome wide
- copy number
- oxidative stress
- endothelial cells
- mitochondrial dna
- mouse model
- spinal cord injury
- cell adhesion
- end stage renal disease
- induced apoptosis
- dna methylation
- genome wide identification
- chronic kidney disease
- newly diagnosed
- prognostic factors
- risk factors
- wound healing
- gene expression
- cell death
- signaling pathway
- transcription factor