Journal Article

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

Miller, E. Nancy, Peacock, Christopher S., Blackwell, Jenefer M., de Roubaix, Lee-Anne, Paul, Malgorzata, Prusa, Andrea-Romana, Thulliez, Philippe, Hargrave, Aubrey C., Meier, Paul, Bessieres, Marie-Hélène, Peyron, François, Coyne, Jessica J., Ferret, Nicole, Petersen, Eskild, Kieffer, François, Nowakowska, Dorota E., Kirisits, Michael J., Tan, Hooi Kuan, Boyer, Kenneth, Gilbert, Ruth E., Cortina-Borja, Mario, Stray-Pedersen, Babill, Mui, Ernest J., Buffolano, Wilma, Jamieson, Sarra E., Wallon, Martine, Cordell, Heather J., Franck, Jacqueline, McLeod, Rima

2008

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: ATP-Binding Cassette Transporters - genetics / Birth / Brain / Brain - pathology / Calcification / Calcification (ectopic) / Children / Childrens health / Clinical outcomes / Cohort Studies / Collagen (type II) / Collagen Type II - genetics / Congenital diseases / Congenital infection / Departments / Development and progression / Diabetes / Diseases / Epidemiology / Epigenesis, Genetic / Epigenetic inheritance / Epigenetics / Eye - pathology / Fetuses / Gene expression / Genetic aspects / Genetics / Genetics and Genomics/Epigenetics / Genetics and Genomics/Genetics of Disease / Genetics and Genomics/Medical Genetics / Genomic Imprinting / Genotype / Heredity / Hospitals / Humans / Hydrocephalus / Immunology / Imprinting / Infants / Infections / Infectious diseases / Infectious Diseases/Epidemiology and Control of Infectious Diseases / Infectious Diseases/Protozoal Infections / Kinases / Lesions / Linkage Disequilibrium / Medical research / Medicine / Mutation / Ophthalmology/Eye Infections / Ophthalmology/Inherited Eye Disorders / Parasites / Parasitic diseases / Pathology/Molecular Pathology / Patient outcomes / Pediatrics / Pregnancy / Public Health and Epidemiology/Infectious Diseases / Retinochoroiditis / Rodents / Toxoplasma gondii / Toxoplasmosis / Toxoplasmosis, Congenital - genetics / Toxoplasmosis, Congenital - pathology / Transcription factors / Treatment Outcome