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

IF 11.4 1区医学 Q1 RHEUMATOLOGY

Arthritis & Rheumatology Pub Date : 2023-05-23 DOI:10.1002/art.42614

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

{"title":"Identification of Distinct Genetic Profiles of Palindromic Rheumatism Using Whole-Exome Sequencing","authors":"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","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Objective</h3>\n \n <p>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).</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>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 (<i>P</i> < 5 × 10<sup>−8</sup>). Furthermore, polygenic risk score analysis showed that PR and RA were not similar (R<sup>2</sup> < 0.025), whereas ACPA+ PR and ACPA− PR showed a moderate genetic correlation (0.38 < R<sup>2</sup> < 0.8).</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>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.</p>\n </section>\n </div>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"75 11","pages":"1947-1957"},"PeriodicalIF":11.4000,"publicationDate":"2023-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Arthritis & Rheumatology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/art.42614","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}

引用次数: 0

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.

查看原文本刊更多论文

应用全外显子组测序鉴定回文性风湿病的不同遗传图谱。

目的：先前的研究强调了复发性风湿病（PR）发病机制中的遗传易感性，但已知的PR基因座只能部分解释该疾病的遗传背景。我们旨在通过全外显子组测序（WES）对PR进行基因鉴定。方法：这项多中心前瞻性研究于2015年9月至2020年1月在10个中国专业风湿病中心进行。对185名PR患者和272名健康对照者进行了WES。PR患者根据ACPA滴度（临界值20 IU/l）分为抗瓜氨酸蛋白抗体（ACPA-）阴性和ACPA（ACPA+）阳性的PR亚组。我们对WES数据进行了全外显子组关联分析。我们使用HLA插补来对HLA基因进行分型。此外，我们使用多基因风险评分来测量PR与类风湿性关节炎（RA）之间的遗传相关性以及ACPA-PR与ACPA+PR之间的遗传关联。结果：在我们研究的185名PR患者中，50名患者（27.02%）为ACPA+，135名PR患者（72.98%）为ACPA-。我们鉴定了8个新的基因座（在ACPA-PR组：ZNF503、RPS6KL1、HOMER3、HLA-DRA；在ACPA+PR组：RPS6KL2、WASH2P、FANK1）和3个HLA等位基因（在ACPA-PR组：HLA-DRB1*0803和HLA-DQB1；在ACPA+PR组：HLA-DPA1*0401），它们与PR相关，并且超过了全基因组显著性（P-8）。此外，多基因风险评分分析显示PR和RA不相似（R22结论：本研究证明了ACPA-和ACPA+PR患者之间存在明显的遗传背景。此外，我们的研究结果强化了PR和RA在基因上不相似。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Arthritis & Rheumatology RHEUMATOLOGY-

CiteScore

20.90

自引率

3.00%

发文量

371

期刊介绍： Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.