title: Human-specific epigenetic variation in the immunological Leukotriene B4 Receptor (LTB4R/BLT1) implicated in common inflammatory diseases.
abstract: BACKGROUND
  Common human diseases are caused by the complex interplay of genetic susceptibility as well as environmental factors. Due to the environment's influence on the epigenome, and therefore genome function, as well as conversely the genome's facilitative effect on the epigenome, analysis of this level of regulation may increase our knowledge of disease pathogenesis.
  
  
  METHODS
  In order to identify human-specific epigenetic influences, we have performed a novel genome-wide DNA methylation analysis comparing human, chimpanzee and rhesus macaque.
  
  
  RESULTS
  We have identified that the immunological Leukotriene B4 receptor (LTB4R, BLT1 receptor) is the most epigenetically divergent human gene in peripheral blood in comparison with other primates. This difference is due to the co-ordinated active state of human-specific hypomethylation in the promoter and human-specific increased gene body methylation. This gene is significant in innate immunity and the LTB4/LTB4R pathway is involved in the pathogenesis of the spectrum of human inflammatory diseases. This finding was confirmed by additional neutrophil-only DNA methylome and lymphoblastoid H3K4me3 chromatin comparative data. Additionally we show through functional analysis that this receptor has increased expression and a higher response to the LTB4 ligand in human versus rhesus macaque peripheral blood mononuclear cells. Genome-wide we also find human species-specific differentially methylated regions (human s-DMRs) are more prevalent in CpG island shores than within the islands themselves, and within the latter are associated with the CTCF motif.
  
  
  CONCLUSIONS
  This result further emphasises the exclusive nature of the human immunological system, its divergent adaptation even from very closely related primates, and the power of comparative epigenomics to identify and understand human uniqueness.
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London, UK ; Current address: Translational Cancer Therapeutics, CR-UK London Research Institute, Lincoln's Inn Fields, London, UK.
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Wilson
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London, UK.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Butcher
authors.affiliation: MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Division of Asthma, Allergy and Lung Biology, King's College London, London, UK.
authors.forename: Holly R
authors.initials: HR
authors.lastname: Foster
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Feber
authors.affiliation: Genebank of Primates and Primate Genetics Laboratory, German Primate Centre, Leibniz Institute for Primate Research, Göttingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Roos
authors.affiliation: Genebank of Primates and Primate Genetics Laboratory, German Primate Centre, Leibniz Institute for Primate Research, Göttingen, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Walter
authors.affiliation: MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Division of Asthma, Allergy and Lung Biology, King's College London, London, UK.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Woszczek
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, London, UK ; Current address: Department of Twin Research & Genetic Epidemiology, St Thomas' Hospital, King's College London, London, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Bell