Biological Sciences Division
Published June 4, 2008 | Version v1
Journal article Open

Genetic and Epigenetic Factors at COL2A1 and ABCA4 Influence Clinical Outcome in Congenital Toxoplasmosis

Creators

  • 1. University of Cambridge
  • 2. University College London
  • 3. University of Chicago
  • 4. Rush University Medical Center
  • 5. CHU Rangueil
  • 6. University of Naples "Frederico II"
  • 7. Hopital Archet II
  • 8. CHU de la Timone
  • 9. Institut de Puériculture
  • 10. Columbia University
  • 11. Medical University
  • 12. University of Medical Sciences

Description

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.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

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Additional details

Identifiers

DOI
10.1371/journal.pone.0002285
Other
oai:uchicago.tind.io:10863

Funding

European Union
BMH4-CT98-3927
European Union
QLG5-CT2000-00846
Department of Health, UK
National Institute of Allergy and Infectious Diseases
TMP 16945 01-20
National Institute of Allergy and Infectious Diseases
27530 01-20
National Institute of Allergy and Infectious Diseases
4328 01-11
National Institute of Allergy and Infectious Diseases
071319-01
FDA
RFA 8-86 01-2
March of Dimes
6-528 01-4
The Research to Prevent Blindness Foundation
United Airlines Foundation
Hyatt Hotels Foundation
Guide Dogs for the Blind Association
The French Consulate in Chicago
Michael Reese Medical Center Foundation
The Buchannan Family Foundation
Kieweit family
Blackmon family
Brennan family
Koshland family
Langel family
Morel family
Rosenstein family
Kapnick family
Cussen family
Taub family
Samuel family
Rooney-Alden family
Foundations of American, Braniff, United, Southwest, Air Canada, Horizon, Brittish, and Pan American Airlines and Angel Flight

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Immunology, Medicine, Ophthalmology and Visual Science, Pediatrics