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Evidence for associations between the purinergic receptor P2X(7) (P2RX7) and toxoplasmosis.

Jamieson SE, Peixoto-Rangel AL, Hargrave AC, Roubaix LA, Mui EJ, Boulter NR, Miller EN, Fuller SJ, Wiley JS, Castellucci L, Boyer K, Peixe RG, Kirisits MJ, Elias Lde S, Coyne JJ, Correa-Oliveira R, Sautter M, Smith NC, Lees MP, Swisher CN, Heydemann P, Noble AG, Patel D, Bardo D, Burrowes D, McLone D, Roizen N, Withers S, Bahia-Oliveira LM, McLeod R, Blackwell JM - Genes Immun. (2010)

Bottom Line: Acquired infection is commonly associated with ocular disease.We found association (FBAT Z-scores +/-2.429; P=0.015) between the derived C(+)G(-) allele (f=0.68; OR=2.06; 95% CI: 1.14-3.75) at single-nucleotide polymorphism (SNP) rs1718119 (1068T>C; Thr-348-Ala), and a second synonymous variant rs1621388 in linkage disequilibrium with it, and clinical signs of disease per se.Analysis of clinical subgroups showed no association with hydrocephalus, with effect sizes for associations with retinal disease and brain calcifications enhanced (OR=3.0-4.25; 0.004<P<0.009) when hydrocephalus was removed from the analysis.

View Article: PubMed Central - PubMed

Affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.

ABSTRACT
Congenital Toxoplasma gondii infection can result in intracranial calcification, hydrocephalus and retinochoroiditis. Acquired infection is commonly associated with ocular disease. Pathology is characterized by strong proinflammatory responses. Ligation of ATP by purinergic receptor P2X(7), encoded by P2RX7, stimulates proinflammatory cytokines and can lead directly to killing of intracellular pathogens. To determine whether P2X(7) has a role in susceptibility to congenital toxoplasmosis, we examined polymorphisms at P2RX7 in 149 child/parent trios from North America. We found association (FBAT Z-scores +/-2.429; P=0.015) between the derived C(+)G(-) allele (f=0.68; OR=2.06; 95% CI: 1.14-3.75) at single-nucleotide polymorphism (SNP) rs1718119 (1068T>C; Thr-348-Ala), and a second synonymous variant rs1621388 in linkage disequilibrium with it, and clinical signs of disease per se. Analysis of clinical subgroups showed no association with hydrocephalus, with effect sizes for associations with retinal disease and brain calcifications enhanced (OR=3.0-4.25; 0.004

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Haploview analysis for D’ and r2 pairwise measures of LD between P2RX7 SNPs in unrelated family founders for (a) NCCCTS and (b) Brazil. D’ values and confidence levels (LOD) are represented as bright red for D’=1, LOD≥2; blue for D’=1, LOD<2; white for D’<1, LOD<2. r2 values are represent as black for r2=1, white for r2=0, with intermediate values for 0<r2<1 indicated by shades of grey. The numbers within the squares represent the D’ or r2 scores for pairwise LD.
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Figure 1: Haploview analysis for D’ and r2 pairwise measures of LD between P2RX7 SNPs in unrelated family founders for (a) NCCCTS and (b) Brazil. D’ values and confidence levels (LOD) are represented as bright red for D’=1, LOD≥2; blue for D’=1, LOD<2; white for D’<1, LOD<2. r2 values are represent as black for r2=1, white for r2=0, with intermediate values for 0<r2<1 indicated by shades of grey. The numbers within the squares represent the D’ or r2 scores for pairwise LD.

Mentions: We first considered the hypothesis that variants at P2RX7 contribute to clinical signs per se following congenital infection with T. gondii. Table 3A presents the results of FBAT analysis when all children from the NCCCTS study were included in the analysis. Only data for the additive model are presented as this model provided the best fit for the observed associations, supported by the finding that the likelihood ratio test performed as part of the parallel conditional logistic regression analysis provided no evidence for dominance effects. SNPs rs28360457 and rs1653624 had insufficient power to contribute to the analysis (MAF<0.1; <10 families contributing to the FBAT analysis). The results across other SNPs indicate the strongest association (Z scores ±2.429; P=0.015) between the non-synonymous SNP rs1718119 and clinical signs associated with T. gondii infection in this population, with significance (Z scores ±2.309; P=0.021) also observed for the synonymous SNP rs1621388. In both cases, disease was associated with the common C(+)/G(−) allele. Pairwise analysis of linkage disequilibrium (LD) between the P2RX7 SNPs in the parents of NCCCTS is presented in figure 1A. Both D’ and r2 statistics provide evidence with statistical confidence (LOD>2) for strong LD (D’=1; r2=0.97) between these two associated SNPs rs1718119 and rs1621388. The difference in statistical significance for the two SNPs in the association data (Table 3A), and the reason why r2 does not equal 1, is due to genotyping failures in some individuals for rs1621388 which reduced by one the number of families contributing to the analysis.


Evidence for associations between the purinergic receptor P2X(7) (P2RX7) and toxoplasmosis.

Jamieson SE, Peixoto-Rangel AL, Hargrave AC, Roubaix LA, Mui EJ, Boulter NR, Miller EN, Fuller SJ, Wiley JS, Castellucci L, Boyer K, Peixe RG, Kirisits MJ, Elias Lde S, Coyne JJ, Correa-Oliveira R, Sautter M, Smith NC, Lees MP, Swisher CN, Heydemann P, Noble AG, Patel D, Bardo D, Burrowes D, McLone D, Roizen N, Withers S, Bahia-Oliveira LM, McLeod R, Blackwell JM - Genes Immun. (2010)

Haploview analysis for D’ and r2 pairwise measures of LD between P2RX7 SNPs in unrelated family founders for (a) NCCCTS and (b) Brazil. D’ values and confidence levels (LOD) are represented as bright red for D’=1, LOD≥2; blue for D’=1, LOD<2; white for D’<1, LOD<2. r2 values are represent as black for r2=1, white for r2=0, with intermediate values for 0<r2<1 indicated by shades of grey. The numbers within the squares represent the D’ or r2 scores for pairwise LD.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908187&req=5

Figure 1: Haploview analysis for D’ and r2 pairwise measures of LD between P2RX7 SNPs in unrelated family founders for (a) NCCCTS and (b) Brazil. D’ values and confidence levels (LOD) are represented as bright red for D’=1, LOD≥2; blue for D’=1, LOD<2; white for D’<1, LOD<2. r2 values are represent as black for r2=1, white for r2=0, with intermediate values for 0<r2<1 indicated by shades of grey. The numbers within the squares represent the D’ or r2 scores for pairwise LD.
Mentions: We first considered the hypothesis that variants at P2RX7 contribute to clinical signs per se following congenital infection with T. gondii. Table 3A presents the results of FBAT analysis when all children from the NCCCTS study were included in the analysis. Only data for the additive model are presented as this model provided the best fit for the observed associations, supported by the finding that the likelihood ratio test performed as part of the parallel conditional logistic regression analysis provided no evidence for dominance effects. SNPs rs28360457 and rs1653624 had insufficient power to contribute to the analysis (MAF<0.1; <10 families contributing to the FBAT analysis). The results across other SNPs indicate the strongest association (Z scores ±2.429; P=0.015) between the non-synonymous SNP rs1718119 and clinical signs associated with T. gondii infection in this population, with significance (Z scores ±2.309; P=0.021) also observed for the synonymous SNP rs1621388. In both cases, disease was associated with the common C(+)/G(−) allele. Pairwise analysis of linkage disequilibrium (LD) between the P2RX7 SNPs in the parents of NCCCTS is presented in figure 1A. Both D’ and r2 statistics provide evidence with statistical confidence (LOD>2) for strong LD (D’=1; r2=0.97) between these two associated SNPs rs1718119 and rs1621388. The difference in statistical significance for the two SNPs in the association data (Table 3A), and the reason why r2 does not equal 1, is due to genotyping failures in some individuals for rs1621388 which reduced by one the number of families contributing to the analysis.

Bottom Line: Acquired infection is commonly associated with ocular disease.We found association (FBAT Z-scores +/-2.429; P=0.015) between the derived C(+)G(-) allele (f=0.68; OR=2.06; 95% CI: 1.14-3.75) at single-nucleotide polymorphism (SNP) rs1718119 (1068T>C; Thr-348-Ala), and a second synonymous variant rs1621388 in linkage disequilibrium with it, and clinical signs of disease per se.Analysis of clinical subgroups showed no association with hydrocephalus, with effect sizes for associations with retinal disease and brain calcifications enhanced (OR=3.0-4.25; 0.004<P<0.009) when hydrocephalus was removed from the analysis.

View Article: PubMed Central - PubMed

Affiliation: Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK.

ABSTRACT
Congenital Toxoplasma gondii infection can result in intracranial calcification, hydrocephalus and retinochoroiditis. Acquired infection is commonly associated with ocular disease. Pathology is characterized by strong proinflammatory responses. Ligation of ATP by purinergic receptor P2X(7), encoded by P2RX7, stimulates proinflammatory cytokines and can lead directly to killing of intracellular pathogens. To determine whether P2X(7) has a role in susceptibility to congenital toxoplasmosis, we examined polymorphisms at P2RX7 in 149 child/parent trios from North America. We found association (FBAT Z-scores +/-2.429; P=0.015) between the derived C(+)G(-) allele (f=0.68; OR=2.06; 95% CI: 1.14-3.75) at single-nucleotide polymorphism (SNP) rs1718119 (1068T>C; Thr-348-Ala), and a second synonymous variant rs1621388 in linkage disequilibrium with it, and clinical signs of disease per se. Analysis of clinical subgroups showed no association with hydrocephalus, with effect sizes for associations with retinal disease and brain calcifications enhanced (OR=3.0-4.25; 0.004

Show MeSH
Related in: MedlinePlus