title: Conjunctival fibrosis and the innate barriers to Chlamydia trachomatis intracellular infection: a genome wide association study.
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.
authors.affiliation: London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Chrissy h
authors.initials: Ch
authors.lastname: Roberts
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Franklin
authors.affiliation: Medical Research Council Unit, The Gambia, Atlantic Boulevard, Fajara, The Gambia.
authors.forename: Pateh
authors.initials: P
authors.lastname: Makalo
authors.affiliation: Medical Research Council Unit, The Gambia, Atlantic Boulevard, Fajara, The Gambia.
authors.forename: Hassan
authors.initials: H
authors.lastname: Joof
authors.affiliation: Medical Research Council Unit, The Gambia, Atlantic Boulevard, Fajara, The Gambia.
authors.forename: Isatou
authors.initials: I
authors.lastname: Sarr
authors.affiliation: Medical Research Council Unit, The Gambia, Atlantic Boulevard, Fajara, The Gambia.
authors.forename: Olaimatu S
authors.initials: OS
authors.lastname: Mahdi
authors.affiliation: National Eye Care Programme, Gambian Ministry of Health, Banjul, The Gambia.
authors.forename: Ansumana
authors.initials: A
authors.lastname: Sillah
authors.affiliation: Sightsavers International, The Gambia. Kairaba Avenue, Banjul, The Gambia.
authors.forename: Momodou
authors.initials: M
authors.lastname: Bah
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: Felicity
authors.initials: F
authors.lastname: Payne
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Jeffreys
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.
authors.forename: William
authors.initials: W
authors.lastname: Bottomley
authors.affiliation: London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Angels
authors.initials: A
authors.lastname: Natividad
authors.affiliation: London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Molina-Gonzalez
authors.affiliation: London School of Hygiene and Tropical Medicine, London, UK.|Medical Research Council Unit, The Gambia, Atlantic Boulevard, Fajara, The Gambia.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Burr
authors.affiliation: London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Preston
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.|Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: Kwiatkowski
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Rockett
authors.affiliation: London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.affiliation: International Centre for Eye Health, London, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Burton
authors.affiliation: London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: David C W
authors.initials: DC
authors.lastname: Mabey
authors.affiliation: London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Bailey
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, UK.|University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK.|NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.affiliation: London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Holland
mesh_terms: D000328:Adult; D002692:Chlamydia trachomatis / Q000276:immunology*; D019295:Computational Biology / Q000379:methods; D003235:Conjunctivitis, Inclusion / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D004198:Disease Susceptibility; D005260:Female; D005355:Fibrosis; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction