Ming Zhao1, Yin Zhou1, Bochen Zhu1, Mengjie Wan1, Tingting Jiang1, Qiqun Tan1, Yan Liu1, Juqing Jiang1, Shuaihantian Luo1, Yixin Tan1, Haijing Wu1, Paul Renauer2, Maria Del Mar Ayala Gutiérrez3, Maria Jesús Castillo Palma4, Rafaela Ortega Castro5, Concepción Fernández-Roldán6, Enrique Raya6, Raquel Faria7, Claudia Carvalho8, Marta E Alarcón-Riquelme9, Zhongyuan Xiang10, Jinwei Chen11, Fen Li11, Guanghui Ling11, Hongjun Zhao12, Xiangping Liao13, Youkun Lin14, Amr H Sawalha2, Qianjin Lu1. 1. Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China. 2. Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. 3. Department of Internal Medicine, Hospital Universitario Carlos Haya, Málaga, Spain. 4. Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Sevilla, Spain. 5. Servicio de Reumatología, Hospital Universitario Reina Sofía, Córdoba, Spain. 6. Departament of Rheumatology, Unidad de Enfermedades Autoinmunes Sistémicas, Hospital Universitario San Cecilio, Granada, Spain. 7. Unidade de Imunologia Clínica/Centro Hospitalar do Porto, Porto, Portugal. 8. Lab Imunogenetics & Autoimmu and NeuroScien, Unidade Multidisciplinar Invest Biomed, Inst Ciencias Biomed Abel Salazar/ Universidade do Porto, Porto, Portugal. 9. Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, Granada, Spain. 10. Department of Clinical Laboratory, The Second Xiangya Hospital of Central South University, Changsha, China. 11. Department of Rheumatology, The Second Xiangya Hospital of Central South University, Changsha, China. 12. Department of Rheumatology, Xiangya Hospital of Central South University, Changsha, China. 13. Department of Nephropathy and Rheumatology, Chenzhou No.1 People's Hospital, Chenzhou, China. 14. Department of Dermatology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Abstract
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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