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Evidence for associations between the purinergic receptor P2X7 (P2RX7) and toxoplasmosis

Genes & Immunity volume 11, pages 374–383 (2010)Cite this article

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Abstract

Congenital Toxoplasma gondii infection can result in intracranial calcification, hydrocephalus and retinochoroiditis. Acquired infection is commonly associated with ocular disease. Pathology is characterized by strong proinflammatory responses. Ligation of ATP by purinergic receptor P2X7, encoded by P2RX7, stimulates proinflammatory cytokines and can lead directly to killing of intracellular pathogens. To determine whether P2X7 has a role in susceptibility to congenital toxoplasmosis, we examined polymorphisms at P2RX7 in 149 child/parent trios from North America. We found association (FBAT Z-scores ±2.429; P=0.015) between the derived C(+)G(−) allele (f=0.68; OR=2.06; 95% CI: 1.14–3.75) at single-nucleotide polymorphism (SNP) rs1718119 (1068T>C; Thr-348-Ala), and a second synonymous variant rs1621388 in linkage disequilibrium with it, and clinical signs of disease per se. Analysis of clinical subgroups showed no association with hydrocephalus, with effect sizes for associations with retinal disease and brain calcifications enhanced (OR=3.0–4.25; 0.004<P<0.009) when hydrocephalus was removed from the analysis. Association with toxoplasmic retinochoroiditis was replicated (FBAT Z-scores ±3.089; P=0.002) in a small family-based study (60 families; 68 affected offspring) of acquired infection in Brazil, where the ancestral T(+) allele (f=0.296) at SNP rs1718119 was strongly protective (OR=0.27; 95% CI: 0.09–0.80).

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Acknowledgements

The clinical evaluation, sample collection and preparation, and parts of the genotyping for the NCCCTS cohort were funded by NIH RO1s NIAID TMP 16945 01-20, 27530 01-20, 4328 01-11, 071319-01, FDA RFA 8-86 01-2; March of Dimes 6-528 01-4; The Research to Prevent Blindness Foundation; United Airlines Foundation; Stanley Foundation; Hyatt Hotels Foundation; gifts from the Morel, Kapnick, Kiewit, Langel, Taub, Rooney-Alden, Schilling, Mann and Cromwell families; and the Finley Samuel Trust. We gratefully acknowledge the patients, their families and their physicians for their participation in the NCCCTS. The many other contributions made to the NCCCTS are acknowledged in full in Cascabulho et al.30 For the Brazilian study we thank the ophthalmologists Dr Daíse Malheiros Meira, Dr Elisa Waked, Dr Fernanda Porto, Dr Fernando Oréfice, Dr Gustavo Heringer and Dr Wesley Campos for examining patients. This research was funded in Brazil by CAPES (BEX 2371/06-05), CNPq (151950/2008-3 and 558876/2008-0) and FAPERJ (E-26/112045/2008). Genetic studies carried out in Cambridge were funded by the Guide Dogs for the Blind Association in the UK. NCS and JSW were supported by an Australian Research Council Discovery Project grant (DP0666515) and MPL was the recipient of a Researcher Exchange, Training and Travel Award from the Australian Research Council/National Health and Research Council Research Network for Parasitology.

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Author notes

  1. S E Jamieson and A L Peixoto-Rangel: These authors are co-first authors.

  2. L M G Bahia-Oliveira, R McLeod and J M Blackwell: These authors contributed equally to this work.

Authors and Affiliations

  1. Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK

    S E Jamieson, A L Peixoto-Rangel, L-A de Roubaix, E N Miller, L Castellucci & J M Blackwell

  2. Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Subiaco, Western Australia, Australia

    S E Jamieson & J M Blackwell

  3. Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes, Reo de Janeiro, Brazil

    A L Peixoto-Rangel, R G Peixe, L de Souza Elias & L M G Bahia-Oliveira

  4. Centro de Pesquisas Rene Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil

    A L Peixoto-Rangel & R Correa-Oliveira

  5. Departments of Ophthalmology, Medicine, Pediatrics, Committees on Immunology, Molecular Medicine, and Genetics Institute of Genomics and Systems Biology, and The College, University of Chicago, and Michael Reese Hospital and Medical Center, Chicago, IL, USA

    A C Hargrave, E J Mui, M J Kirisits, J J Coyne, M Sautter, A G Noble, D Patel, D Bardo, D Burrowes, N Roizen, S Withers & R McLeod

  6. Institute for the Biotechnology of Infectious Diseases, University of Technology, Sydney, New South Wales, Australia

    N R Boulter, N C Smith & M P Lees

  7. Nepean Clinical School, Nepean Hospital, University of Sydney, Penrith, New South Wales, Australia

    S J Fuller & J S Wiley

  8. Federal University of Bahia, Salvador, Bahia, Brazil

    L Castellucci

  9. Division of Pediatric Infectious Diseases, Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA

    K Boyer & P Heydemann

  10. Department of Pediatric Neurology, Northwestern Children's Hospital, Chicago, IL, USA

    C N Swisher, A G Noble & D McLone

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  1. S E Jamieson
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  2. A L Peixoto-Rangel
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Correspondence to J M Blackwell.

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Jamieson, S., Peixoto-Rangel, A., Hargrave, A. et al. Evidence for associations between the purinergic receptor P2X7 (P2RX7) and toxoplasmosis. Genes Immun 11, 374–383 (2010). https://doi.org/10.1038/gene.2010.31

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