Li Ying, Lai-Han Leung Elaine, Pan Hudan, Yao Xiaojun, Huang Qingchun, Wu Min, Xu Ting, Wang Yuwei, Cai Jun, Li Runze, Liu Wei, Liu Liang
State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, China.
Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China.
Oncotarget. 2017 Nov 22;8(67):111119-111129. doi: 10.18632/oncotarget.22630. eCollection 2017 Dec 19.
Rheumatoid arthritis (RA) is a highly prevalent chronic autoimmune disease. However, genetic and environmental factors involved in RA pathogenesis are still remained largely unknown. To identify the genetic causal variants underlying pathogenesis and disease progression of RA patients, we undertook the first comprehensive whole-exome sequencing (WES) study in a total of 124 subjects including 58 RA cases and 66 healthy controls in Han Chinese population. We identified 378 novel genes that were enriched with deleterious variants in RA patients using a gene burden test. The further functional effects of associated genetic genes were classified and assessed, including 21 newly identified genes that were involved in the extracellular matrix (ECM)-receptor interaction, protein digestion and absorption, focal adhesion and glycerophospholipid metabolism pathways relevant to RA pathogenesis. Moreover, six pathogenic variants were investigated and structural analysis predicted their potentially functional alteration by homology modeling. Importantly, five novel and rare homozygous variants (, , , and ) were identified, which may exhibit more functional impact on RA pathogenesis. Notably, 7 genes involved in the olfactory transduction pathway were enriched and associated with RA disease progression. Therefore, we performed an efficient and powerful technique WES in Chinese RA patients and identified novel, rare and common disease causing genes that alter innate immunity pathways and contribute to the risk of RA. Findings in this study may provide potential diagnostic tools and therapeutic strategies for RA patients.
类风湿性关节炎（RA）是一种高度流行的慢性自身免疫性疾病。然而，参与RA发病机制的遗传和环境因素在很大程度上仍不清楚。为了确定RA患者发病机制和疾病进展背后的遗传因果变异，我们在124名受试者中开展了首次全面的全外显子组测序（WES）研究，其中包括58例RA患者和66名汉族健康对照。我们使用基因负担测试在RA患者中鉴定出378个富含有害变异的新基因。对相关遗传基因的进一步功能效应进行了分类和评估，包括21个新鉴定的基因，它们参与了与RA发病机制相关的细胞外基质（ECM）-受体相互作用、蛋白质消化和吸收、粘着斑和甘油磷脂代谢途径。此外，研究了六个致病变异，并通过同源建模预测了它们潜在的功能改变。重要的是，鉴定出五个新的罕见纯合变异（、、、和），它们可能对RA发病机制表现出更大的功能影响。值得注意的是，参与嗅觉转导途径的7个基因富集并与RA疾病进展相关。因此，我们在中国RA患者中进行了高效且强大的WES技术，并鉴定出改变固有免疫途径并导致RA风险的新的、罕见的和常见的致病基因。本研究的结果可能为RA患者提供潜在的诊断工具和治疗策略。
