Research Papers:

Identification of potential genetic causal variants for rheumatoid arthritis by whole-exome sequencing

Ying Li, Elaine Lai-Han Leung, Hudan Pan, Xiaojun Yao, Qingchun Huang, Min Wu, Ting Xu, Yuwei Wang, Jun Cai, Runze Li, Wei Liu and Liang Liu _

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Oncotarget. 2017; 8:111119-111129. https://doi.org/10.18632/oncotarget.22630

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Ying Li1,*, Elaine Lai-Han Leung1,*, Hudan Pan1, Xiaojun Yao1, Qingchun Huang2, Min Wu3, Ting Xu3, Yuwei Wang1, Jun Cai1, Runze Li1, Wei Liu4 and Liang Liu1

1State 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

2Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China

3The Third Affiliated Hospital of Soochow University, Changzhou, China

4The First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China

*These authors have contributed equally to this work

Correspondence to:

Liang Liu, email: [email protected]

Keywords: rheumatoid arthritis; whole-exome sequencing; Chinese population; genetic causal variants; homology modeling

Received: July 29, 2017    Accepted: September 23, 2017    Published: November 22, 2017


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 (NCR3LG1, RAP1GAP, CHCHD5, HIPK2 and DIAPH2) 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.

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