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Ann. Rheum. Dis., Jan 29 2025, S0003-4967(25)00069-X | https://doi.org/10.1016/j.ard.2025.01.015
Genetic burden of lupus increases the risk of transition from normal to preclinical autoimmune conditions via antinuclear antibody development
Sehwan Chun 1†, So-Young Bang 2,3,4†, Ayeong Kwon 1, Chan Young Kim 1, Soojin Cha 3,4, Young-Chang Kwon 3,4, Young Bin Joo 2,3, Soo-Kyung Cho 2,3, Chan-Bum Choi 2,3, Yoon-Kyoung Sung 2,3, Ji-Young Han 5, Tae-Hwan Kim 2,3, Jae-Bum Jun 2,3, Dae Hyun Yoo 2,3, Hye-Soon Lee 2,3,4, Kwangwoo Kim 1,6, Sang-Cheol Bae 2,3,4
1Department of Biology, Kyung Hee University, Seoul, Republic of Korea
2Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea
3Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
4Hanyang Institute of Bioscience and Biotechnology, Seoul, Republic of Korea
5Department of Periodontology, Division of Dentistry, Hanyang University, College of Medicine, Seoul, Republic of Korea
6Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, Republic of Korea
†SC and S-YB contributed equally.
Correspondence to Dr. Kwangwoo Kim, Dr. Sang-Cheol Bae
1Department of Biology, Kyung Hee University, Seoul, Republic of Korea
2Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea
3Hanyang University Institute for Rheumatology Research, Seoul, Republic of Korea
4Hanyang Institute of Bioscience and Biotechnology, Seoul, Republic of Korea
5Department of Periodontology, Division of Dentistry, Hanyang University, College of Medicine, Seoul, Republic of Korea
6Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, Republic of Korea
†SC and S-YB contributed equally.
Correspondence to Dr. Kwangwoo Kim, Dr. Sang-Cheol Bae
Abstract
Objectives: This study aimed to investigate the association between the genetic burden of systemic lupus erythematosus (SLE) and the loss of tolerance to self-nuclear antigens in the preclinical stage.
Methods: We analysed genetic data from 349 Korean individuals who tested positive for autoantibodies in the preclinical stage, along with 33,596 healthy controls and 2057 patients with SLE. Genome-wide and pathway-specific polygenic risk scores (PRSs) of SLE were calculated based on 180 known non-human leukocyte antigen (non-HLA) SLE loci, HLA-DRB1 classical alleles, and predefined immune-related pathways to subsequently correlate with clinical phenotypes, particularly the presence of antinuclear antibodies (ANAs) at various titre thresholds.
Results: Individuals with preclinical autoimmune conditions exhibited significantly higher SLE PRSs than healthy controls (P = 2.99 × 10-5), with a significantly upward trend between ANA titres and PRS (P = 1.12 × 10-3). Stratification analysis revealed that preclinical-stage individuals with PRSs exceeding the means of age- and sex-matched PRSs among patients with SLE were at a significantly higher risk of ANA development (odds ratio = 2.25; P = 8.12 × 10-3 at a dilution factor of 1:80). Pathway-specific PRS analysis identified the significant enrichment of SLE-risk effects in nine pathways, such as signalling related to reactive oxygen species production, T cell receptor, B cell receptor, and cytokines, in ANA-positive preclinical individuals (Padjusted < 0.05).
Conclusions: Our findings illustrate that the genetic burden of SLE may lead to a crucial transition from normal to preclinical autoimmune conditions prior to the pathogenic stage by increasing the susceptibility to and levels of ANAs.
Methods: We analysed genetic data from 349 Korean individuals who tested positive for autoantibodies in the preclinical stage, along with 33,596 healthy controls and 2057 patients with SLE. Genome-wide and pathway-specific polygenic risk scores (PRSs) of SLE were calculated based on 180 known non-human leukocyte antigen (non-HLA) SLE loci, HLA-DRB1 classical alleles, and predefined immune-related pathways to subsequently correlate with clinical phenotypes, particularly the presence of antinuclear antibodies (ANAs) at various titre thresholds.
Results: Individuals with preclinical autoimmune conditions exhibited significantly higher SLE PRSs than healthy controls (P = 2.99 × 10-5), with a significantly upward trend between ANA titres and PRS (P = 1.12 × 10-3). Stratification analysis revealed that preclinical-stage individuals with PRSs exceeding the means of age- and sex-matched PRSs among patients with SLE were at a significantly higher risk of ANA development (odds ratio = 2.25; P = 8.12 × 10-3 at a dilution factor of 1:80). Pathway-specific PRS analysis identified the significant enrichment of SLE-risk effects in nine pathways, such as signalling related to reactive oxygen species production, T cell receptor, B cell receptor, and cytokines, in ANA-positive preclinical individuals (Padjusted < 0.05).
Conclusions: Our findings illustrate that the genetic burden of SLE may lead to a crucial transition from normal to preclinical autoimmune conditions prior to the pathogenic stage by increasing the susceptibility to and levels of ANAs.
논문정보
- Research article
- 2025년 01월 (BRIC 등록일 2025-02-05)
- 국내 연구진
- 의약학 > 유전 및 유전체의학
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