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Genetic and epigenetic factors at COL2A1 and ABCA4 influence clinical outcome in congenital toxoplasmosis

Lookup NU author(s): Professor Heather Cordell

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Abstract

Background: Primary Toxoplasma gondii infection during pregnancy can be transmitted to the fetus. At birth, infected infants may have intracranial calcification, hydrocephalus, and retinochoroiditis, and new ocular lesions can occur at any age after birth. Not all children who acquire infection in utero develop these clinical signs of disease. Whilst severity of disease is influenced by trimester in which infection is acquired by the mother, other factors including genetic predisposition may contribute. Methods and Findings: In 457 mother-child pairs from Europe, and 149 child/parent trios from North America, we show that ocular and brain disease in congenital toxoplasmosis associate with polymorphisms in ABCA4 encoding ATP-binding cassette transporter, subfamily A, member 4. Polymorphisms at COL2A1 encoding type II collagen associate only with ocular disease. Both loci showed unusual inheritance patterns for the disease allele when comparing outcomes in heterozygous affected children with outcomes in affected children of heterozygous mothers. Modeling suggested either an effect of mother's genotype, or parent-of-origin effects. Experimental studies showed that both ABCA4 and COL2A1 show isoform-specific epigenetic modifications consistent with imprinting. Conclusions: These associations between clinical outcomes of congenital toxoplasmosis and polymorphisms at ABCA4 and COL2A1 provide novel insight into the molecular pathways that can be affected by congenital infection with this parasite. © 2008 Jamieson et al.


Publication metadata

Author(s): Jamieson SE, de Roubaix L-A, Cortina-Borja M, Tan HK, Mui EJ, Cordell HJ, Kirisits MJ, Miller EN, Peacock CS, Hargrave AC, Coyne JJ, Boyer K, Bessieres M-H, Buffolano W, Ferret N, Franck J, Kieffer F, Meier P, Nowakowska DE, Paul M, Peyron F, Stray-Pedersen B, Prusa A-R, Thulliez P, Wallon M, Petersen E, McLeod R, Gilbert RE, Blackwell JM

Publication type: Article

Publication status: Published

Journal: PLoS ONE

Year: 2008

Volume: 3

Issue: 6

Print publication date: 04/06/2008

Date deposited: 01/02/2010

ISSN (electronic): 1932-6203

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pone.0002285

DOI: 10.1371/journal.pone.0002285

PubMed id: 18523590


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Funding

Funder referenceFunder name
Hyatt Hotels Foundation
Michael Reese Medical Center Foundation
The Buchannan Family Foundation
The French Consulate in Chicago
Department of Health, UK
The Research to Prevent Blindness Foundation
United Airlines Foundation
071319-01NIH
27530 01-20NIH
16945 01-20NIH
4328 01-11NIH
8-86 01-2FDA RFA
6-528 01-4March of Dimes
BMH4-CT98-3927EU
QLG5-CT2000-00846EU

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