Host genetic and epigenetic factors in toxoplasmosis

Abstract

Analysing human genetic variation provides a powerful tool in understanding risk factors for disease. Toxoplasma gondii acquired by the mother can be transmitted to the fetus. Infants with the most severe clinical signs in brain and eye are those infected early in pregnancy when fetal immunity is least well developed. Genetic analysis could provide unique insight into events in utero that are otherwise difficult to determine. We tested the hypothesis that propensity for T. gondii to cause eye disease is associated with genes previously implicated in congenital or juvenile onset ocular disease. Using mother-child pairs from Europe (EMSCOT) and child/parent trios from North America (NCCCTS), we demonstrated that ocular and brain disease in congenital toxoplasmosis associate with polymorphisms in ABCA4 encoding ATP-binding cassette transporter, subfamily A, member 4 previously associated with juvenile onset retinal dystrophies including Stargardt's disease. Polymorphisms at COL2A1 encoding type II collagen, previously associated with Stickler syndrome, associated only with ocular disease in congenital toxoplasmosis. Experimental studies showed that both ABCA4 and COL2A1 show isoform-specific epigenetic modifications consistent with imprinting, which provided an explanation for the patterns of inheritance observed. These genetic and epigenetic risk factors provide unique insight into molecular pathways in the pathogenesis of disease.

Fig. 1

experimental evidence for monoallelic expression at ABCA4 and COL2A1. A and B show sequence analysis of genomic DNA (gDNA) and cDNA in EBV lines heterozygous for exonic SNPs. A: EBV lines heterozygous for ABCA4 rs3112831 in gDNA; lines EBV1 to EBV4 homozygous (i.e. monoallelic) in cDNA specific for the exon 10-containing isoform. Line EBV5 is heterozygous, indicating that monoallelic silencing is polymorphic; B: EBV lines show monoallelic expression for COL2A1 SNP rs3737548 in PCR products specific for isoform IIB, but not IIA. Positions of SNPs (*) indicated by N where heterozygous, with the bp underlined for monoallelic expression in cDNA. Adapted from Jamieson et al. (2008).

Fig. 2

percent power (Y-axis) of N = 500 (A) or N=1000 (B, C) trios of case-control pairs to detect allelic association for a risk allele with effect size (OR) 1.5 (A, C) or 2 (B), given different risk allele frequencies (X-axis) and p values (10^-2-10^-7 as indicated on key for different lines on each graph). Greater robustness to type one error, i.e. lower thresholds for p values, is required for GWAS.