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Conjunctival fibrosis and the innate barriers to Chlamydia trachomatis intracellular infection: a genome wide association study.

Roberts Ch, Franklin CS, Makalo P, Joof H, Sarr I, Mahdi OS, Sillah A, Bah M, Payne F, Jeffreys AE, Bottomley W, Natividad A, Molina-Gonzalez S, Burr SE, Preston M, Kwiatkowski D, Rockett KA, Clark TG, Burton MJ, Mabey DC, Bailey R, Barroso I, Holland MJ - Sci Rep (2015)

Bottom Line: The most strongly associated SNP (rs111513399, P = 5.38 × 10(-7)) fell within a gene (PREX2) with homology to factors known to facilitate chlamydial entry to the host cell.Pathway analysis of GWAS data was significantly enriched for mitotic cell cycle processes (P = 0.001), the immune response (P = 0.00001) and for multiple cell surface receptor signalling pathways.Although unconfirmed, the data suggest that genetic associations with chlamydial scarring disease may be focussed on processes relating to the immune response, the host cell cycle and cell surface receptor signalling.

View Article: PubMed Central - PubMed

Affiliation: London School of Hygiene and Tropical Medicine, London, UK.

ABSTRACT
Chlamydia trachomatis causes both trachoma and sexually transmitted infections. These diseases have similar pathology and potentially similar genetic predisposing factors. We aimed to identify polymorphisms and pathways associated with pathological sequelae of ocular Chlamydia trachomatis infections in The Gambia. We report a discovery phase genome-wide association study (GWAS) of scarring trachoma (1090 cases, 1531 controls) that identified 27 SNPs with strong, but not genome-wide significant, association with disease (5 × 10(-6) > P > 5 × 10(-8)). The most strongly associated SNP (rs111513399, P = 5.38 × 10(-7)) fell within a gene (PREX2) with homology to factors known to facilitate chlamydial entry to the host cell. Pathway analysis of GWAS data was significantly enriched for mitotic cell cycle processes (P = 0.001), the immune response (P = 0.00001) and for multiple cell surface receptor signalling pathways. New analyses of published transcriptome data sets from Gambia, Tanzania and Ethiopia also revealed that the same cell cycle and immune response pathways were enriched at the transcriptional level in various disease states. Although unconfirmed, the data suggest that genetic associations with chlamydial scarring disease may be focussed on processes relating to the immune response, the host cell cycle and cell surface receptor signalling.

No MeSH data available.


Related in: MedlinePlus

Summary of pathways analysis with ALIGATOR and PODA.Blue circle shows root level Reactome hierarchy event terms and stableidentifiers with at least one significant pathway under ALIGATOR. Red circleshows same for PODA analysis. Six branches contained significant pathwaysunder both analyses. Ten branches contained no significant pathways ineither analysis.
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f3: Summary of pathways analysis with ALIGATOR and PODA.Blue circle shows root level Reactome hierarchy event terms and stableidentifiers with at least one significant pathway under ALIGATOR. Red circleshows same for PODA analysis. Six branches contained significant pathwaysunder both analyses. Ten branches contained no significant pathways ineither analysis.

Mentions: One-hundred-and-three Reactome pathways had an ALIGATOR P value(PALIGATOR) ≦0.05 after a pre-screening round of 100permutations. Eighty-four candidate pathways had P after 100,000 permutations(P100k) ≦ 0.05 (Table 2). Reactome is arranged in an event hierarchy, astructured relationship table where related pathways share parent terms andwhere all pathways belong to one of 23 root level event terms. The significantpathways in the ALIGATOR analysis all came under one of nine root level eventterms (Cell cycle, Developmental Biology, Disease, Immune system, Metabolism,Metabolism of proteins, Programmed Cell Death, Signal Transduction,Trans-membrane transport of small molecules; Fig. 3). Themost significant pathway (P = 0.00001) related to thebiology of the innate and adaptive cellular immune response (Table 2), followed by the adaptive response(P = 0.00023) and a number of highly significant andclosely related pathways relating to polymorphism in the Fibroblast GrowthFactor receptors (FGFR) and their ligands (minimumP = 0.00028). Other significant pathways includedmitotic cell cycle processes and several signal transduction pathways, includingmultiple pathways relating to G-protein coupled receptors (GPCR), Epidermalgrowth factor receptors (EGFR) and the insulin-like growth factor receptor(IGFR1). The “Disease” pathways appeared to besynonymous with the FGFR pathways.


Conjunctival fibrosis and the innate barriers to Chlamydia trachomatis intracellular infection: a genome wide association study.

Roberts Ch, Franklin CS, Makalo P, Joof H, Sarr I, Mahdi OS, Sillah A, Bah M, Payne F, Jeffreys AE, Bottomley W, Natividad A, Molina-Gonzalez S, Burr SE, Preston M, Kwiatkowski D, Rockett KA, Clark TG, Burton MJ, Mabey DC, Bailey R, Barroso I, Holland MJ - Sci Rep (2015)

Summary of pathways analysis with ALIGATOR and PODA.Blue circle shows root level Reactome hierarchy event terms and stableidentifiers with at least one significant pathway under ALIGATOR. Red circleshows same for PODA analysis. Six branches contained significant pathwaysunder both analyses. Ten branches contained no significant pathways ineither analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663496&req=5

f3: Summary of pathways analysis with ALIGATOR and PODA.Blue circle shows root level Reactome hierarchy event terms and stableidentifiers with at least one significant pathway under ALIGATOR. Red circleshows same for PODA analysis. Six branches contained significant pathwaysunder both analyses. Ten branches contained no significant pathways ineither analysis.
Mentions: One-hundred-and-three Reactome pathways had an ALIGATOR P value(PALIGATOR) ≦0.05 after a pre-screening round of 100permutations. Eighty-four candidate pathways had P after 100,000 permutations(P100k) ≦ 0.05 (Table 2). Reactome is arranged in an event hierarchy, astructured relationship table where related pathways share parent terms andwhere all pathways belong to one of 23 root level event terms. The significantpathways in the ALIGATOR analysis all came under one of nine root level eventterms (Cell cycle, Developmental Biology, Disease, Immune system, Metabolism,Metabolism of proteins, Programmed Cell Death, Signal Transduction,Trans-membrane transport of small molecules; Fig. 3). Themost significant pathway (P = 0.00001) related to thebiology of the innate and adaptive cellular immune response (Table 2), followed by the adaptive response(P = 0.00023) and a number of highly significant andclosely related pathways relating to polymorphism in the Fibroblast GrowthFactor receptors (FGFR) and their ligands (minimumP = 0.00028). Other significant pathways includedmitotic cell cycle processes and several signal transduction pathways, includingmultiple pathways relating to G-protein coupled receptors (GPCR), Epidermalgrowth factor receptors (EGFR) and the insulin-like growth factor receptor(IGFR1). The “Disease” pathways appeared to besynonymous with the FGFR pathways.

Bottom Line: The most strongly associated SNP (rs111513399, P = 5.38 × 10(-7)) fell within a gene (PREX2) with homology to factors known to facilitate chlamydial entry to the host cell.Pathway analysis of GWAS data was significantly enriched for mitotic cell cycle processes (P = 0.001), the immune response (P = 0.00001) and for multiple cell surface receptor signalling pathways.Although unconfirmed, the data suggest that genetic associations with chlamydial scarring disease may be focussed on processes relating to the immune response, the host cell cycle and cell surface receptor signalling.

View Article: PubMed Central - PubMed

Affiliation: London School of Hygiene and Tropical Medicine, London, UK.

ABSTRACT
Chlamydia trachomatis causes both trachoma and sexually transmitted infections. These diseases have similar pathology and potentially similar genetic predisposing factors. We aimed to identify polymorphisms and pathways associated with pathological sequelae of ocular Chlamydia trachomatis infections in The Gambia. We report a discovery phase genome-wide association study (GWAS) of scarring trachoma (1090 cases, 1531 controls) that identified 27 SNPs with strong, but not genome-wide significant, association with disease (5 × 10(-6) > P > 5 × 10(-8)). The most strongly associated SNP (rs111513399, P = 5.38 × 10(-7)) fell within a gene (PREX2) with homology to factors known to facilitate chlamydial entry to the host cell. Pathway analysis of GWAS data was significantly enriched for mitotic cell cycle processes (P = 0.001), the immune response (P = 0.00001) and for multiple cell surface receptor signalling pathways. New analyses of published transcriptome data sets from Gambia, Tanzania and Ethiopia also revealed that the same cell cycle and immune response pathways were enriched at the transcriptional level in various disease states. Although unconfirmed, the data suggest that genetic associations with chlamydial scarring disease may be focussed on processes relating to the immune response, the host cell cycle and cell surface receptor signalling.

No MeSH data available.


Related in: MedlinePlus