Exome Sequencing Reveals Genetic Variability and Identifies Chronic Prognostic Loci in Chinese Sarcoidosis Patients

Qian Zhang; Hui Huang; Meijun Zhang; Chuling Fang; Na Wang; Xiaoyan Jing; Jian Guo; Wei Sun; Xiaoyu Yang; Zuojun Xu

doi:10.3389/fonc.2022.910227

Exome Sequencing Reveals Genetic Variability and Identifies Chronic Prognostic Loci in Chinese Sarcoidosis Patients

Front Oncol. 2022 Jul 4:12:910227. doi: 10.3389/fonc.2022.910227. eCollection 2022.

Authors

Qian Zhang¹, Hui Huang¹, Meijun Zhang², Chuling Fang¹, Na Wang¹, Xiaoyan Jing¹, Jian Guo¹, Wei Sun¹, Xiaoyu Yang¹, Zuojun Xu¹

Affiliations

¹ Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
² ANNOROAD Co., Beijing, China.

Abstract

Background: Sarcoidosis is an inflammatory disease characterized by non-caseating granuloma formation in various organs, with several recognized genetic and environmental risk factors. Despite substantial progress, the genetic determinants associated with its prognosis remain largely unknown.

Objectives: This study aimed to identify the genetic changes involved in sarcoidosis and evaluate their clinical relevance.

Methods: We performed whole-exome sequencing (WES) in 116 sporadic sarcoidosis patients (acute sarcoidosis patients, n=58; chronic sarcoidosis patients, n=58). In addition, 208 healthy controls were selected from 1000 G East Asian population data. To identify genes enriched in sarcoidosis, Fisher exact tests were performed. The identified genes were included for further pathway analysis using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, we used the STRING database to construct a protein network of rare variants and Cytoscape to identify hub genes of signaling pathways.

Results: WES and Fisher's exact test identified 1,311 variants in 439 protein-coding genes. A total of 135 single nucleotide polymorphisms (SNPs) on 30 protein-coding genes involved in the immunological process based on the GO and KEGG enrichment analysis. Pathway enrichment analysis showed osteoclast differentiation and cytokine-cytokine receptor interactions. Three missense mutations (rs76740888, rs149664918, and rs78251590) in two genes (PRSS3 and CNN2) of immune-related genes showed significantly different mutation frequencies between the disease group and healthy controls. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis of the clinical features and mutation loci showed that the missense variant (rs76740888, Chr9:33796673 G>A) of PRSS3 [p=0.04, odds ratio (OR) = 2.49] was significantly associated with chronic disease prognosis. Additionally, the top two hub genes were CCL4 and CXCR4 based on protein-protein interaction (PPI) network analysis.

Conclusion: Our study provides new insights into the molecular pathogenesis of sarcoidosis and identifies novel genetic alterations in this disease, especially PRSS3, which may be promising targets for future therapeutic strategies for chronic sarcoidosis.

Keywords: adaptive immune response; chronic sarcoidosis prognosis; non-synonymous mutations; sarcoidosis; whole-exome sequencing.