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 Bedri & 25 others Jan Hillert, Carlos Matute, Alfredo Antiguedad, ANZgene Consortium, Alan G. Baxter, Allan G. Kermode, Bruce Taylor, David R. Booth, Deborah F. Mason, Graeme J. Stewart, Helmut Butzkueven, Jac C. Charlesworth, James Wiley, Lotti Tajouri, Lyn R. Griffiths, Mark Slee, Matthew A. Brown, Pablo Moscato, Rodney J. Scott, Simon A. Broadley, Steve Vucic, Trevor J. Kilpatrick, William M. Carrol, Michael H. Barnett, James S. Wiley

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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.

Original languageEnglish
Article numberddv278
Pages (from-to)5644-5654
Number of pages11
JournalHuman Molecular Genetics
Volume24
Issue number19
DOIs
Publication statusPublished - 1 Oct 2015

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Multiple Sclerosis
Odds Ratio
Purinergic P2X7 Receptors
HLA-DRB1 Chains
Ethidium
Central Nervous System Diseases
Oligodendroglia
Genetic Association Studies
Demyelinating Diseases
Heterozygote
Gene Frequency
Haplotypes
Meta-Analysis
Monocytes
Adenosine Triphosphate
Alleles
Macrophages
Binding Sites
Ligands
Population

Cite this

Gu, B. J., Field, J., Dutertre, S., Ou, A., Kilpatrick, T. J., Lechner-Scott, J., ... Wiley, J. S. (2015). A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis. Human Molecular Genetics, 24(19), 5644-5654. [ddv278]. https://doi.org/10.1093/hmg/ddv278
Gu, Ben J. ; Field, Judith ; Dutertre, Sébastien ; Ou, Amber ; Kilpatrick, Trevor J. ; Lechner-Scott, Jeannette ; Scott, Rodney J. ; Lea, Rodney A. ; Taylor, Bruce V. ; Stankovich, Jim ; Butzkueven, Helmut ; Gresle, Melissa ; Laws, Simon M. ; Petrou, Steven ; Hoffjan, Sabine ; Akkad, Denis A. ; Graham, Colin A. ; Hawkins, Stanley ; Glaser, Anna ; Bedri, Sahl Khalid ; Hillert, Jan ; Matute, Carlos ; Antiguedad, Alfredo ; ANZgene Consortium ; Baxter, Alan G. ; Kermode, Allan G. ; Taylor, Bruce ; Booth, David R. ; Mason, Deborah F. ; Stewart, Graeme J. ; Butzkueven, Helmut ; Charlesworth, Jac C. ; Wiley, James ; Tajouri, Lotti ; Griffiths, Lyn R. ; Slee, Mark ; Brown, Matthew A. ; Moscato, Pablo ; Scott, Rodney J. ; Broadley, Simon A. ; Vucic, Steve ; Kilpatrick, Trevor J. ; Carrol, William M. ; Barnett, Michael H. ; Wiley, James S. / A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 19. pp. 5644-5654.
@article{b3a5a6da361e4c2a873e88f0d3277aaf,
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 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 {\AA} 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.",
author = "Gu, {Ben J.} and Judith Field and S{\'e}bastien Dutertre and Amber Ou and Kilpatrick, {Trevor J.} and Jeannette Lechner-Scott and Scott, {Rodney J.} and Lea, {Rodney A.} and Taylor, {Bruce V.} and Jim Stankovich and Helmut Butzkueven and Melissa Gresle and Laws, {Simon M.} and Steven Petrou and Sabine Hoffjan and Akkad, {Denis A.} and Graham, {Colin A.} and Stanley Hawkins and Anna Glaser and Bedri, {Sahl Khalid} and Jan Hillert and Carlos Matute and Alfredo Antiguedad and {ANZgene Consortium} and Baxter, {Alan G.} and Kermode, {Allan G.} and Bruce Taylor and Booth, {David R.} and Mason, {Deborah F.} and Stewart, {Graeme J.} and Helmut Butzkueven and Charlesworth, {Jac C.} and James Wiley and Lotti Tajouri and Griffiths, {Lyn R.} and Mark Slee and Brown, {Matthew A.} and Pablo Moscato and Scott, {Rodney J.} and Broadley, {Simon A.} and Steve Vucic and Kilpatrick, {Trevor J.} and Carrol, {William M.} and Barnett, {Michael H.} and Wiley, {James S.}",
year = "2015",
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doi = "10.1093/hmg/ddv278",
language = "English",
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Gu, BJ, Field, J, Dutertre, S, Ou, A, Kilpatrick, TJ, Lechner-Scott, J, Scott, RJ, Lea, RA, Taylor, BV, Stankovich, J, 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, ANZgene Consortium, Baxter, AG, Kermode, AG, Taylor, B, Booth, DR, Mason, DF, Stewart, GJ, Butzkueven, H, Charlesworth, JC, Wiley, J, Tajouri, L, Griffiths, LR, Slee, M, Brown, MA, Moscato, P, Scott, RJ, Broadley, SA, Vucic, S, Kilpatrick, TJ, Carrol, WM, Barnett, MH & Wiley, JS 2015, 'A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis' Human Molecular Genetics, vol. 24, no. 19, ddv278, pp. 5644-5654. https://doi.org/10.1093/hmg/ddv278

A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis. / Gu, Ben J.; Field, Judith; Dutertre, Sébastien; Ou, Amber; Kilpatrick, Trevor J.; Lechner-Scott, Jeannette; Scott, Rodney J.; Lea, Rodney A.; Taylor, Bruce V.; Stankovich, Jim; Butzkueven, Helmut; Gresle, Melissa; Laws, Simon M.; Petrou, Steven; Hoffjan, Sabine; Akkad, Denis A.; Graham, Colin A.; Hawkins, Stanley; Glaser, Anna; Bedri, Sahl Khalid; Hillert, Jan; Matute, Carlos; Antiguedad, Alfredo; ANZgene Consortium; Baxter, Alan G. (Group Author); Kermode, Allan G. (Group Author); Taylor, Bruce (Group Author); Booth, David R. (Group Author); Mason, Deborah F. (Group Author); Stewart, Graeme J. (Group Author); Butzkueven, Helmut (Group Author); Charlesworth, Jac C. (Group Author); Wiley, James (Group Author); Tajouri, Lotti (Group Author); Griffiths, Lyn R. (Group Author); Slee, Mark (Group Author); Brown, Matthew A. (Group Author); Moscato, Pablo (Group Author); Scott, Rodney J. (Group Author); Broadley, Simon A. (Group Author); Vucic, Steve (Group Author); Kilpatrick, Trevor J. (Group Author); Carrol, William M. (Group Author); Barnett, Michael H. (Group Author); Wiley, James S.

In: Human Molecular Genetics, Vol. 24, No. 19, ddv278, 01.10.2015, p. 5644-5654.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

AU - Gu, Ben J.

AU - Field, Judith

AU - Dutertre, Sébastien

AU - Ou, Amber

AU - Kilpatrick, Trevor J.

AU - Lechner-Scott, Jeannette

AU - Scott, Rodney J.

AU - Lea, Rodney A.

AU - Taylor, Bruce V.

AU - Stankovich, Jim

AU - Butzkueven, Helmut

AU - Gresle, Melissa

AU - Laws, Simon M.

AU - Petrou, Steven

AU - Hoffjan, Sabine

AU - Akkad, Denis A.

AU - Graham, Colin A.

AU - Hawkins, Stanley

AU - Glaser, Anna

AU - Bedri, Sahl Khalid

AU - Hillert, Jan

AU - Matute, Carlos

AU - Antiguedad, Alfredo

AU - ANZgene Consortium

AU - Baxter, Alan G.

AU - Kermode, Allan G.

AU - Taylor, Bruce

AU - Booth, David R.

AU - Mason, Deborah F.

AU - Stewart, Graeme J.

AU - Butzkueven, Helmut

AU - Charlesworth, Jac C.

AU - Wiley, James

AU - Tajouri, Lotti

AU - Griffiths, Lyn R.

AU - Slee, Mark

AU - Brown, Matthew A.

AU - Moscato, Pablo

AU - Scott, Rodney J.

AU - Broadley, Simon A.

AU - Vucic, Steve

AU - Kilpatrick, Trevor J.

AU - Carrol, William M.

AU - Barnett, Michael H.

AU - Wiley, James S.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84943748673&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddv278

DO - 10.1093/hmg/ddv278

M3 - Article

VL - 24

SP - 5644

EP - 5654

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 19

M1 - ddv278

ER -