A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis
Authors
Ben J. Gu
Judith Field
Sebastien Dutertre
Amber Ou
Trevor J. Kilpatrick
Jeannette Lechner-Scott
Rodney Scott
Rodney Lea
Bruce V. Taylor
Jim Stankovich
Helmut Butzkueven
Melissa Gresle
Simon M. Laws, Edith Cowan UniversityFollow
Steven Petrou
Sabine Hoffjan
Denis A. Akkad
Colin A. Graham
Stanley Hawkins
Anna Glaser
Sahl Khalid Bedri
Jan Hillert
Carlos Matute
Alfredo Antiguedad
Alan G. Baxter
Allan G. Kermode
David R. Booth
Deborah F. Mason
Graeme J. Stewart
Jac C. Charlesworth
Lotti Tajouri
Lyn R. Griffiths
Mark Slee
Matthew A. Brown
Pablo Moscato, Edith Cowan University
Simon A. Broadley
Steve Vucic
William M. Carroll
Michael Barnett
James S. Wiley
Document Type
Journal Article
Publisher
Oxford University Press
School
School of Medical Sciences / Centre of Excellence for Alzheimer's Disease Research and Care
RAS ID
19873
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 byATP-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.
DOI
10.1093/hmg/ddv278
Access Rights
free_to_read
Comments
Gu, B.J., Field, J., Dutertre, S., Ou, A., Kilpatrick, T.J., Lechner-Scott, J., ...& Barnett, M.H. (2015). A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis in Human Molecular Genetics, 24(19), 5644-5654. Available here.