Objective Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease with limited reliable diagnostic biomarkers. We investigated whether gene methylation could meet sensitivity and specificity criteria for a robust biomarker.
Methods IFI44L promoter methylation was examined using DNA samples from a discovery set including 377 patients with SLE, 358 healthy controls (HCs) and 353 patients with rheumatoid arthritis (RA). Two independent sets including 1144 patients with SLE, 1350 HCs, 429 patients with RA and 199 patients with primary Sjögren's syndrome (pSS) were used for validation.
Results Significant hypomethylation of two CpG sites within IFI44L promoter, Site1 (Chr1: 79 085 222) and Site2 (Chr1: 79 085 250; cg06872964), was identified in patients with SLE compared with HCs, patients with RA and patients with pSS. In a comparison between patients with SLE and HCs included in the first validation cohort, Site1 methylation had a sensitivity of 93.6% and a specificity of 96.8% at a cut-off methylation level of 75.5% and Site2 methylation had a sensitivity of 94.1% and a specificity of 98.2% at a cut-off methylation level of 25.5%. The IFI44L promoter methylation marker was also validated in an European-derived cohort. In addition, the methylation levels of Site1 and Site2 within IFI44L promoter were significantly lower in patients with SLE with renal damage than those without renal damage. Patients with SLE showed significantly increased methylation levels of Site1 and Site2 during remission compared with active stage.
Conclusions The methylation level of IFI44L promoter can distinguish patients with SLE from healthy persons and other autoimmune diseases, and is a highly sensitive and specific diagnostic marker for SLE.
- Systemic Lupus Erythematosus
- Autoimmune Diseases
- Gene Polymorphism
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Handling editor Tore K Kvien
Contributors MZ, QL and AHS designed and performed the experiments, analysed the data and drafted the manuscript; YZ, BZ, MW, TJ, QT, YL, JJ, SL, YT, HW, PR, MdMAG, MJCP, ROC, CF-R, ER, RF, CC, MEA-R, ZX, JC, FL, GL, HZ, XL and YL performed sample collection and the experiments.
Funding This work was supported by the National Natural Science Foundation of China (No. 81220108017, No. 81430074, No. 81270024 and No. 81522038), the Hunan Provincial Natural Science Foundation of China (14JJ1009), the National Key Clinical Speciality Construction Project of National Health and Family Planning Commission of the People's Republic of China, and the National Institute of Allergy and Infectious Diseases, NIH under award number R01AI097134.
Competing interests None declared.
Ethics approval The ethical committee of the Second Xiangya Hospital of Central South University and the ethics committees and institutional review boards at all the authors’ institutions approved this study.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All data are available from the corresponding author upon request.
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