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.
Details
Title
Genetic and Epigenetic Factors at COL2A1 and ABCA4 Influence Clinical Outcome in Congenital Toxoplasmosis
Author
Jamieson, Sarra E. : University of Cambridge de Roubaix, Lee-Anne : University of Cambridge Cortina-Borja, Mario : University College London Tan, Hooi Kuan : University College London Mui, Ernest J. : University of Chicago Cordell, Heather J. : University of Cambridge Kirisits, Michael J. : University of Chicago Miller, E. Nancy : University of Cambridge Peacock, Christopher S. : University of Cambridge Hargrave, Aubrey C. : University of Chicago Coyne, Jessica J. : University of Chicago Boyer, Kenneth : Rush University Medical Center Bessieres, Marie-Hélène : CHU Rangueil Buffolano, Wilma : University of Naples "Frederico II" Ferret, Nicole : Hopital Archet II Franck, Jacqueline : CHU de la Timone Kieffer, François : Institut de Puériculture Meier, Paul : Columbia University Nowakowska, Dorota E. : Medical University Paul, Malgorzata : University of Medical Sciences
Funding Information
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
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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.