Identification of Distinct Genetic Profiles of Palindromic Rheumatism Using Whole-Exome Sequencing

Chenxiang Zheng; Fan Wang; Yue Sun; Zhuochao Zhou; Yijun You; Dongyi He; Xiaoxia Zhu; Lindi Jiang; Cui Lu; Lijun Wu; Hongzhi Wang; Hanying Mei; Ting Zeng; Hui Zheng; Jialing Teng; Honglei Liu; Xiaobing Cheng; Yutong Su; Hui Shi; Qiongyi Hu; Xueming Jian; Aamir Fahira; Qiangzhen Yang; Ke Wang; Yanqin Wen; Zhuo Wang; Jinyan Huang; Chengde Yang; Yongyong Shi; Junna Ye

doi:10.1002/art.42614

Identification of Distinct Genetic Profiles of Palindromic Rheumatism Using Whole-Exome Sequencing

Arthritis Rheumatol. 2023 Nov;75(11):1947-1957. doi: 10.1002/art.42614. Epub 2023 Sep 20.

Authors

Chenxiang Zheng^#¹, Fan Wang^#², Yue Sun², Zhuochao Zhou², Yijun You², Dongyi He³, Xiaoxia Zhu⁴, Lindi Jiang⁵, Cui Lu⁶, Lijun Wu⁷, Hongzhi Wang⁸, Hanying Mei⁹, Ting Zeng¹⁰, Hui Zheng¹¹, Jialing Teng², Honglei Liu², Xiaobing Cheng², Yutong Su², Hui Shi², Qiongyi Hu², Xueming Jian¹, Aamir Fahira¹, Qiangzhen Yang¹, Ke Wang¹, Yanqin Wen¹, Zhuo Wang¹, Jinyan Huang¹², Chengde Yang², Yongyong Shi¹³, Junna Ye²

Affiliations

¹ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China.
² Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁴ Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China.
⁵ Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China.
⁶ Department of Haematology and Rheumatology, Shanghai Songjiang District Central Hospital, Shanghai, PR China.
⁷ Department of Rheumatology and Immunology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China.
⁸ Department of Rheumatology, Affiliated Hospital of Jiaxing University, The First Hospital of Jiaxing, Jiaxing, Zhejiang, China.
⁹ Department of Rheumatology and Immunology, Affiliated Jiujiang Hospital of Nanchang University, Jiujiang, Jiangxi, China.
¹⁰ Rheumatology Department, Xinhua Hospital Chongming Branch, Shanghai, China.
¹¹ The Second Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.
¹² Biomedical Big Data Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
¹³ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China.

^# Contributed equally.

PMID: 37219934
DOI: 10.1002/art.42614

Abstract

Objective: Previous studies have underlined the genetic susceptibility in the pathogenesis of palindromic rheumatism (PR), but the known PR loci only partially explain the disease's genetic background. We aimed to genetically identify PR by whole-exome sequencing (WES).

Methods: This multicenter prospective study was conducted in 10 Chinese specialized rheumatology centers between September 2015 and January 2020. WES was performed in 185 patients with PR and in 272 healthy controls. PR patients were divided into PR subgroups who were negative for anti-citrullinated protein antibody (ACPA-) and positive for ACPA (ACPA+) according to ACPA titer (cutoff value 20 IU/liter). We conducted whole-exome association analysis for the WES data. We used HLA imputation to type HLA genes. In addition, we used the polygenic risk score to measure the genetic correlations between PR and rheumatoid arthritis (RA) and the genetic correlations between ACPA- PR and ACPA+ PR.

Results: Among 185 patients with PR enrolled in our study, 50 patients (27.02%) were ACPA+ and 135 PR patients (72.98%) were ACPA-. We identified 8 novel loci (in the ACPA- PR group: ZNF503, RPS6KL1, HOMER3, HLA-DRA; in the ACPA+ PR group: RPS6KL1, TNPO2, WASH2P, FANK1) and 3 HLA alleles (in the ACPA- PR group: HLA-DRB1*0803 and HLA-DQB1; in the ACPA+ PR group: HLA-DPA1*0401) that were associated with PR and that surpassed genome-wide significance (P < 5 × 10^-8 ). Furthermore, polygenic risk score analysis showed that PR and RA were not similar (R² < 0.025), whereas ACPA+ PR and ACPA- PR showed a moderate genetic correlation (0.38 < R² < 0.8).

Conclusion: This study demonstrated the distinct genetic background between ACPA- and ACPA+ PR patients. Additionally, our findings strengthened that PR and RA were not genetically similar.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Arthritis, Rheumatoid* / genetics
Autoantibodies*
Exome Sequencing
Genetic Predisposition to Disease
Genetic Profile
Genotype
HLA-DRB1 Chains / genetics
Humans
Peptides, Cyclic
Prospective Studies

Substances

Autoantibodies
Peptides, Cyclic
HLA-DRB1 Chains

Supplementary concepts

Palindromic rheumatism