title: IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus.
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.
authors.affiliation: Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Bochen
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Wan
authors.affiliation: Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Qiqun
authors.initials: Q
authors.lastname: Tan
authors.affiliation: Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Juqing
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Shuaihantian
authors.initials: S
authors.lastname: Luo
authors.affiliation: Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Haijing
authors.initials: H
authors.lastname: Wu
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Renauer
authors.affiliation: Department of Internal Medicine, Hospital Universitario Carlos Haya, Málaga, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Del Mar Ayala Gutiérrez
authors.affiliation: Department of Internal Medicine, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
authors.forename: Maria Jesús
authors.initials: MJ
authors.lastname: Castillo Palma
authors.affiliation: Servicio de Reumatología, Hospital Universitario Reina Sofía, Córdoba, Spain.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Ortega Castro
authors.affiliation: Departament of Rheumatology, Unidad de Enfermedades Autoinmunes Sistémicas, Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Fernández-Roldán
authors.affiliation: Departament of Rheumatology, Unidad de Enfermedades Autoinmunes Sistémicas, Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Raya
authors.affiliation: Unidade de Imunologia Clínica/Centro Hospitalar do Porto, Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Faria
authors.affiliation: Lab Imunogenetics & Autoimmu and NeuroScien, Unidade Multidisciplinar Invest Biomed, Inst Ciencias Biomed Abel Salazar/ Universidade do Porto, Porto, Portugal.
authors.forename: Claudia
authors.initials: C
authors.lastname: Carvalho
authors.affiliation: 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.
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcón-Riquelme
authors.affiliation: Department of Clinical Laboratory, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Department of Rheumatology, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Jinwei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Rheumatology, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Rheumatology, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Ling
authors.affiliation: Department of Rheumatology, Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Nephropathy and Rheumatology, Chenzhou No.1 People's Hospital, Chenzhou, China.
authors.forename: Xiangping
authors.initials: X
authors.lastname: Liao
authors.affiliation: Department of Dermatology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
authors.forename: Youkun
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
authors.affiliation: Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Qianjin
authors.initials: Q
authors.lastname: Lu
mesh_terms: D000328:Adult; D000941:Antigens / Q000097:blood / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D003598:Cytoskeletal Proteins / Q000097:blood / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012680:Sensitivity and Specificity; D012859:Sjogren's Syndrome / Q000097:blood / Q000175:diagnosis / Q000235:genetics
chemical_list: D000941:Antigens; D015415:Biomarkers; D003598:Cytoskeletal Proteins; D005819:Genetic Markers; C065888:IFI44 protein, human
keywords: Autoimmune Diseases; Gene Polymorphism; Systemic Lupus Erythematosus