title: A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis.
abstract: Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case-control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of 'pore' function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln-270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory 'pore' function.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Gu
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Judith
authors.initials: J
authors.lastname: Field
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR 5247, Université Montpellier 2-CNRS, Montpellier, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dutertre
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Amber
authors.initials: A
authors.lastname: Ou
authors.affiliation: Melbourne Neuroscience Institute, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Kilpatrick
authors.affiliation: Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Lechner-Scott
authors.affiliation: Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Rodney
authors.initials: R
authors.lastname: Scott
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
authors.forename: Rodney
authors.initials: R
authors.lastname: Lea
authors.affiliation: Menzies Institute, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Bruce V
authors.initials: BV
authors.lastname: Taylor
authors.affiliation: Menzies Institute, University of Tasmania, Hobart, Tasmania, Australia.
authors.forename: Jim
authors.initials: J
authors.lastname: Stankovich
authors.affiliation: Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Helmut
authors.initials: H
authors.lastname: Butzkueven
authors.affiliation: Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Gresle
authors.affiliation: School of Medical Sciences, Edith Cowan University, Joondalup, Western Australia, Australia.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Laws
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.affiliation: Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hoffjan
authors.affiliation: Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany.
authors.forename: Denis A
authors.initials: DA
authors.lastname: Akkad
authors.affiliation: Regional Genetics Laboratories, Belfast Health & Social Care Trust, Northern Ireland, UK.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Graham
authors.affiliation: Department of Neurology, Belfast Health & Social Care Trust, Northern Ireland, UK.
authors.forename: Stanley
authors.initials: S
authors.lastname: Hawkins
authors.affiliation: Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Glaser
authors.affiliation: Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sahl Khalid
authors.initials: SK
authors.lastname: Bedri
authors.affiliation: Department of Clinical Neurosciences, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
authors.affiliation: CIBERNED, Achucarro Basque Center for Neuroscience, and Departamento de Neurociencias, Universidad del País Vasco, Leioa, Spain and.
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
authors.affiliation: Servicio de Neurología, Hospital Universitario Basurto-Osakidetza, Bilbao, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Antiguedad
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia, james.wiley@florey.edu.au.
authors.forename: James S
authors.initials: JS
authors.lastname: Wiley
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D019943:Amino Acid Substitution; D001120:Arginine / Q000378:metabolism; D044362:Australasia; D001665:Binding Sites; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058486:Receptors, Purinergic P2X7 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D044465:White People / Q000235:genetics
chemical_list: C546468:P2RX7 protein, human; D058486:Receptors, Purinergic P2X7; D005973:Glutamine; D000255:Adenosine Triphosphate; D001120:Arginine