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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

Trachoma associated genes and pathways.Potential roles for candidate genes (red) that were identified through thisGWAS are indicated. Various significant cell surface receptors pathwaysincluding FGFR, GPCR, ILGFR1 and GLPR1 are linked to cell cycle control byPI3K/Akt/p53 signalling. Chlamydial elementary bodies are known to interactwith this system via sos1 and vav2. Downstream signalling from thesepathways can lead to actin remodelling (facilitating cell entry), cell cyclearrest and inhibition of apoptosis; all factors that facilitate parasitism.Glucose and sodium ion homeostasis resulting from p53/cell-cycle control mayincrease nutrient availability to the growing inclusion. Up-regulation ofNFKB, CTGF, MMP9 and TGFB are potential routes tofibrosis.
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f5: Trachoma associated genes and pathways.Potential roles for candidate genes (red) that were identified through thisGWAS are indicated. Various significant cell surface receptors pathwaysincluding FGFR, GPCR, ILGFR1 and GLPR1 are linked to cell cycle control byPI3K/Akt/p53 signalling. Chlamydial elementary bodies are known to interactwith this system via sos1 and vav2. Downstream signalling from thesepathways can lead to actin remodelling (facilitating cell entry), cell cyclearrest and inhibition of apoptosis; all factors that facilitate parasitism.Glucose and sodium ion homeostasis resulting from p53/cell-cycle control mayincrease nutrient availability to the growing inclusion. Up-regulation ofNFKB, CTGF, MMP9 and TGFB are potential routes tofibrosis.

Mentions: Many of the prioritized SNPs, genes and pathways that we identified in this study areknown to be functionally linked to one another, as well as to systems that are knownto be involved in trachomatous scar formation. A simplified summary of theseinteractions is presented in Fig. 5, which is derived from ourown data and from multiple publicly available open databases (e.g. Genecards, NCBI,Reactome and others). The figure, which shows the convergence of the systems onpathways of cell cycle control, is a model building interpretation of our resultsthat requires experimental validation.


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)

Trachoma associated genes and pathways.Potential roles for candidate genes (red) that were identified through thisGWAS are indicated. Various significant cell surface receptors pathwaysincluding FGFR, GPCR, ILGFR1 and GLPR1 are linked to cell cycle control byPI3K/Akt/p53 signalling. Chlamydial elementary bodies are known to interactwith this system via sos1 and vav2. Downstream signalling from thesepathways can lead to actin remodelling (facilitating cell entry), cell cyclearrest and inhibition of apoptosis; all factors that facilitate parasitism.Glucose and sodium ion homeostasis resulting from p53/cell-cycle control mayincrease nutrient availability to the growing inclusion. Up-regulation ofNFKB, CTGF, MMP9 and TGFB are potential routes tofibrosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Trachoma associated genes and pathways.Potential roles for candidate genes (red) that were identified through thisGWAS are indicated. Various significant cell surface receptors pathwaysincluding FGFR, GPCR, ILGFR1 and GLPR1 are linked to cell cycle control byPI3K/Akt/p53 signalling. Chlamydial elementary bodies are known to interactwith this system via sos1 and vav2. Downstream signalling from thesepathways can lead to actin remodelling (facilitating cell entry), cell cyclearrest and inhibition of apoptosis; all factors that facilitate parasitism.Glucose and sodium ion homeostasis resulting from p53/cell-cycle control mayincrease nutrient availability to the growing inclusion. Up-regulation ofNFKB, CTGF, MMP9 and TGFB are potential routes tofibrosis.
Mentions: Many of the prioritized SNPs, genes and pathways that we identified in this study areknown to be functionally linked to one another, as well as to systems that are knownto be involved in trachomatous scar formation. A simplified summary of theseinteractions is presented in Fig. 5, which is derived from ourown data and from multiple publicly available open databases (e.g. Genecards, NCBI,Reactome and others). The figure, which shows the convergence of the systems onpathways of cell cycle control, is a model building interpretation of our resultsthat requires experimental validation.

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