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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

PREX2 is closely involved in processes surrounding TARP mediated Chlamydialentry.Downstream signalling via RAC leads to changes in cell cycle control andactin skeleton rearrangements that facilitate infection. PREX2 canindirectly mediate downstream changes to cell cycle control and glucosehomeostasis via RAC and Akt/p53.
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f4: PREX2 is closely involved in processes surrounding TARP mediated Chlamydialentry.Downstream signalling via RAC leads to changes in cell cycle control andactin skeleton rearrangements that facilitate infection. PREX2 canindirectly mediate downstream changes to cell cycle control and glucosehomeostasis via RAC and Akt/p53.

Mentions: The leading SNP-identified candidate gene from this study was PREX2(Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2), aGuanine Nucleotide Exchange Factor (GNEF) and G-protein coupled receptor (G-PCR).PREX2 is known to interact with both Rac and the PI3K inhibitor PTEN29 (Fig. 4). Other GNEFs acting upstream of PI3K and Rac havebeen shown to directly interact with chlamydial TARP30, a keymolecule that transduces the earliest signals between the chlamydial body and thehost cell31. PREX2 variants may therefore play a key role inprotecting the host cell from Ct entry.


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)

PREX2 is closely involved in processes surrounding TARP mediated Chlamydialentry.Downstream signalling via RAC leads to changes in cell cycle control andactin skeleton rearrangements that facilitate infection. PREX2 canindirectly mediate downstream changes to cell cycle control and glucosehomeostasis via RAC and Akt/p53.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: PREX2 is closely involved in processes surrounding TARP mediated Chlamydialentry.Downstream signalling via RAC leads to changes in cell cycle control andactin skeleton rearrangements that facilitate infection. PREX2 canindirectly mediate downstream changes to cell cycle control and glucosehomeostasis via RAC and Akt/p53.
Mentions: The leading SNP-identified candidate gene from this study was PREX2(Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2), aGuanine Nucleotide Exchange Factor (GNEF) and G-protein coupled receptor (G-PCR).PREX2 is known to interact with both Rac and the PI3K inhibitor PTEN29 (Fig. 4). Other GNEFs acting upstream of PI3K and Rac havebeen shown to directly interact with chlamydial TARP30, a keymolecule that transduces the earliest signals between the chlamydial body and thehost cell31. PREX2 variants may therefore play a key role inprotecting the host cell from Ct entry.

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