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

journal contribution
posted on 2023-05-18, 13:23 authored by Gu, BJ, Field, J, Dutertre, S, Ou, A, Kilpatrick, TJ, Lechner-Scott, J, Scott, R, Lea, R, Bruce TaylorBruce Taylor, Jim Stankovich, Butzkueven, H, Gresle, M, Laws, SM, Petrou, S, Hoffjan, S, Akkad, DA, Graham, CA, Hawkins, S, Glaser, A, Bedri, SK, Hillert, J, Matute, C, Antiguedad, A, Wiley, JS
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.

History

Publication title

Human Molecular Genetics

Volume

24

Issue

19

Pagination

5644-5654

ISSN

0964-6906

Department/School

Menzies Institute for Medical Research

Publisher

Oxford Univ Press

Place of publication

Great Clarendon St, Oxford, England, Ox2 6Dp

Rights statement

Copyright 2015 The Author

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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    University Of Tasmania

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