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IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus
  1. Ming Zhao1,
  2. Yin Zhou1,
  3. Bochen Zhu1,
  4. Mengjie Wan1,
  5. Tingting Jiang1,
  6. Qiqun Tan1,
  7. Yan Liu1,
  8. Juqing Jiang1,
  9. Shuaihantian Luo1,
  10. Yixin Tan1,
  11. Haijing Wu1,
  12. Paul Renauer2,
  13. Maria del Mar Ayala Gutiérrez3,
  14. Maria Jesús Castillo Palma4,
  15. Rafaela Ortega Castro5,
  16. Concepción Fernández-Roldán6,
  17. Enrique Raya6,
  18. Raquel Faria7,
  19. Claudia Carvalho8,
  20. Marta E Alarcón-Riquelme9,10,
  21. Zhongyuan Xiang11,
  22. Jinwei Chen12,
  23. Fen Li12,
  24. Guanghui Ling12,
  25. Hongjun Zhao13,
  26. Xiangping Liao14,
  27. Youkun Lin15,
  28. Amr H Sawalha2,
  29. Qianjin Lu1
  1. 1Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China
  2. 2Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  3. 3Department of Internal Medicine, Hospital Universitario Carlos Haya, Málaga, Spain
  4. 4Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Sevilla, Spain
  5. 5Servicio de Reumatología, Hospital Universitario Reina Sofía, Córdoba, Spain
  6. 6Departament of Rheumatology, Unidad de Enfermedades Autoinmunes Sistémicas, Hospital Universitario San Cecilio, Granada, Spain
  7. 7Unidade de Imunologia Clínica/Centro Hospitalar do Porto, Porto, Portugal
  8. 8Lab Imunogenetics & Autoimmu and NeuroScien, Unidade Multidisciplinar Invest Biomed, Inst Ciencias Biomed Abel Salazar/ Universidade do Porto, Porto, Portugal
  9. 9Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  10. 10Centre for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Health Sciences Technology Park, Granada, Spain
  11. 11Department of Clinical Laboratory, The Second Xiangya Hospital of Central South University, Changsha, China
  12. 12Department of Rheumatology, The Second Xiangya Hospital of Central South University, Changsha, China
  13. 13Department of Rheumatology, Xiangya Hospital of Central South University, Changsha, China
  14. 14Department of Nephropathy and Rheumatology, Chenzhou No.1 People's Hospital, Chenzhou, China
  15. 15Department of Dermatology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
  1. Correspondence to Dr Qianjin Lu, Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha 410011, China; qianlu5860{at}gmail.com; or Dr. Amr H. Sawalha, Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; asawalha@umich.edu.

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.

  • Systemic Lupus Erythematosus
  • Autoimmune Diseases
  • Gene Polymorphism

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