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

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

Chenxiang Zheng #  1 , Fan Wang #  2 , Yue Sun  2 , Zhuochao Zhou  2 , Yijun You  2 , Dongyi He  3 , Xiaoxia Zhu  4 , Lindi Jiang  5 , Cui Lu  6 , Lijun Wu  7 , Hongzhi Wang  8 , Hanying Mei  9 , Ting Zeng  10 , Hui Zheng  11 , Jialing Teng  2 , Honglei Liu  2 , Xiaobing Cheng  2 , Yutong Su  2 , Hui Shi  2 , Qiongyi Hu  2 , Xueming Jian  1 , Aamir Fahira  1 , Qiangzhen Yang  1 , Ke Wang  1 , Yanqin Wen  1 , Zhuo Wang  1 , Jinyan Huang  12 , Chengde Yang  2 , Yongyong Shi  13 , Junna Ye  2
Affiliations
Multicenter Study

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

Chenxiang Zheng et al. Arthritis Rheumatol. 2023 Nov.

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.

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References

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