A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Ben J. Gu, Judith Field, Sébastien Dutertre, Amber Ou, Trevor J. Kilpatrick, Jeannette Lechner-Scott, Rodney J. Scott, Rodney A. Lea, Bruce V. Taylor, Jim Stankovich, Helmut Butzkueven, Melissa Gresle, Simon M. Laws, Steven Petrou, Sabine Hoffjan, Denis A. Akkad, Colin A. Graham, Stanley Hawkins, Anna Glaser, Sahl Khalid BedriJan Hillert, Carlos Matute, Alfredo Antiguedad, ANZgene Consortium, Alan G. Baxter (Group Author), Allan G. Kermode (Group Author), Bruce Taylor (Group Author), David R. Booth (Group Author), Deborah F. Mason (Group Author), Graeme J. Stewart (Group Author), Helmut Butzkueven (Group Author), Jac C. Charlesworth (Group Author), James Wiley (Group Author), Lotti Tajouri (Group Author), Lyn R. Griffiths (Group Author), Mark Slee (Group Author), Matthew A. Brown (Group Author), Pablo Moscato (Group Author), Rodney J. Scott (Group Author), Simon A. Broadley (Group Author), Steve Vucic (Group Author), Trevor J. Kilpatrick (Group Author), William M. Carrol (Group Author), Michael H. Barnett (Group Author), James S. Wiley*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

50 Citations (Scopus)


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.

Original languageEnglish
Article numberddv278
Pages (from-to)5644-5654
Number of pages11
JournalHuman Molecular Genetics
Issue number19
Publication statusPublished - 1 Oct 2015


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