title: DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease.
abstract: BACKGROUND
  Chronic hepatitis B infection is characterized by hepatic immune and inflammatory response with considerable variation in the rates of progression to cirrhosis. Genetic variants and environmental cues influence predisposition to the development of chronic liver disease; however, it remains unknown if aberrant DNA methylation is associated with fibrosis progression in chronic hepatitis B.
  
  
  RESULTS
  To identify epigenetic marks associated with inflammatory and fibrotic processes of the hepatitis B-induced chronic liver disease, we carried out hepatic genome-wide methylation profiling using Illumina Infinium BeadArrays comparing mild and severe fibrotic disease in a discovery cohort of 29 patients. We obtained 310 differentially methylated regions and selected four loci comprising three genes from the top differentially methylated regions: hypermethylation of HOXA2 and HDAC4 along with hypomethylation of PPP1R18 were significantly linked to severe fibrosis. We replicated the prominent methylation marks in an independent cohort of 102 patients by bisulfite modification and pyrosequencing. The timing and causal relationship of epigenetic modifications with disease severity was further investigated using a cohort of patients with serial biopsies.
  
  
  CONCLUSIONS
  Our findings suggest a linkage of widespread epigenetic dysregulation with disease progression in chronic hepatitis B infection. CpG methylation at novel genes sheds light on new molecular pathways, which can be potentially exploited as a biomarker or targeted to attenuate inflammation and fibrosis.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|School of Medicine, Koç University Hospital, Koç University, 4th floor- M-4220. Davutpaşa Caddesi no: 4, 34010 Istanbul, Turkey.
authors.forename: Müjdat
authors.initials: M
authors.lastname: Zeybel
authors.affiliation: Department of Gastroenterology and Hepatology, Katip Çelebi University, Atatürk Eğitim ve Araştırma Hastanesi, Izmir, Turkey.
authors.forename: Sezgin
authors.initials: S
authors.lastname: Vatansever
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hardy
authors.affiliation: Department of Pathology, Katip Çelebi University, Atatürk Eğitim ve Araştırma Hastanesi, Izmir, Turkey.
authors.forename: Ayşegül Akder
authors.initials: AA
authors.lastname: Sarı
authors.affiliation: Department of Pathology, Katip Çelebi University, Atatürk Eğitim ve Araştırma Hastanesi, Izmir, Turkey.
authors.forename: Fulya
authors.initials: F
authors.lastname: Cakalağaoğlu
authors.affiliation: Department of Pathology, Katip Çelebi University, Atatürk Eğitim ve Araştırma Hastanesi, Izmir, Turkey.
authors.forename: Arzu
authors.initials: A
authors.lastname: Avcı
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Gemma Louise
authors.initials: GL
authors.lastname: Zeybel
authors.affiliation: School of Medicine, Koç University Hospital, Koç University, 4th floor- M-4220. Davutpaşa Caddesi no: 4, 34010 Istanbul, Turkey.
authors.forename: Serçin
authors.initials: S
authors.lastname: Karahüseyinoğlu
authors.affiliation: Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bashton
authors.affiliation: Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Mathers
authors.affiliation: Department of Gastroenterology and Hepatology, Katip Çelebi University, Atatürk Eğitim ve Araştırma Hastanesi, Izmir, Turkey.
authors.forename: Belkıs
authors.initials: B
authors.lastname: Ünsal
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Jelena
authors.initials: J
authors.lastname: Mann
mesh_terms: D000328:Adult; D000368:Aged; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000235:genetics*; D006655:Histone Deacetylases / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D054645:Protein Phosphatase 1 / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics
chemical_list: D005819:Genetic Markers; C520321:HOXA2 protein, human; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C520010:PPP1R18 protein, human; D054645:Protein Phosphatase 1; C400300:HDAC4 protein, human; D006655:Histone Deacetylases
keywords: Cirrhosis; DNA methylation; Epigenetics; Hepatitis B infection; Liver fibrosis