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


RESULTS
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.
Jamieson
Sarra E
SE
Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Cambridge, United Kingdom.
de Roubaix
Lee-Anne
LA
Cortina-Borja
Mario
M
Tan
Hooi Kuan
HK
Mui
Ernest J
EJ
Cordell
Heather J
HJ
Kirisits
Michael J
MJ
Miller
E Nancy
EN
Peacock
Christopher S
CS
Hargrave
Aubrey C
AC
Coyne
Jessica J
JJ
Boyer
Kenneth
K
Bessieres
Marie-Hélène
MH
Buffolano
Wilma
W
Ferret
Nicole
N
Franck
Jacqueline
J
Kieffer
François
F
Meier
Paul
P
Nowakowska
Dorota E
DE
Paul
Malgorzata
M
Peyron
François
F
Stray-Pedersen
Babill
B
Prusa
Andrea-Romana
AR
Thulliez
Philippe
P
Wallon
Martine
M
Petersen
Eskild
E
McLeod
Rima
R
Gilbert
Ruth E
RE
Blackwell
Jenefer M
JM
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D001921:Brain / Q000473:pathology; D015331:Cohort Studies; D024043:Collagen Type II / Q000235:genetics*; D044127:Epigenesis, Genetic; D005123:Eye / Q000473:pathology; D018392:Genomic Imprinting; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D014125:Toxoplasmosis, Congenital / Q000235:genetics* / Q000473:pathology; D016896:Treatment Outcome
C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; C499177:COL2A1 protein, human; D024043:Collagen Type II