title: Innate immunity in ocular Chlamydia trachomatis infection: contribution of IL8 and CSF2 gene variants to risk of trachomatous scarring in Gambians.
abstract: BACKGROUND
  Trachoma, a chronic keratoconjunctivitis caused by Chlamydia trachomatis, is the world's commonest infectious cause of blindness. Blindness is due to progressive scarring of the conjunctiva (trachomatous scarring) leading to in-turning of eyelashes (trichiasis) and corneal opacification. We evaluated the contribution of genetic variation across the chemokine and cytokine clusters in chromosomes 4q and 5q31 respectively to risk of scarring trachoma and trichiasis in a large case-control association study in a Gambian population.
  
  
  METHODS
  Linkage disequilibrium (LD) mapping was used to investigate risk effects across the 4q and 5q31 cytokine clusters in relation to the risk of scarring sequelae of ocular Ct infection. Disease association and epistatic effects were assessed in a population based study of 651 case-control pairs by conditional logistic regression (CLR) analyses.
  
  
  RESULTS
  LD mapping suggested that genetic effects on risk within these regions mapped to the pro-inflammatory innate immune genes interleukin 8 (IL8) and granulocyte-macrophage colony stimulatory factor (CSF2) loci. The IL8-251 rare allele (IL8-251 TT) was associated with protection from scarring trachoma (OR = 0.29 p = 0.027). The intronic CSF2_27348 A allele in chromosome 5q31 was associated with dose dependent protection from trichiasis, with each copy of the allele reducing risk by 37% (p = 0.005). There was evidence of epistasis, with effects at IL8 and CSF2 loci interacting with those previously reported at the MMP9 locus, a gene acting downstream to IL8 and CSF2 in the inflammatory cascade.
  
  
  CONCLUSIONS
  innate immune response SNP-haplotypes are linked to ocular Ct sequelae. This work illustrates the first example of epistatic effects of two genes on trachoma.
authors.affiliation: London School of Hygiene and Tropical Medicine, London University, London, UK. angels.natividad@inserm.fr
authors.forename: Angels
authors.initials: A
authors.lastname: Natividad
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hull
authors.forename: Gaia
authors.initials: G
authors.lastname: Luoni
authors.forename: Martin
authors.initials: M
authors.lastname: Holland
authors.forename: Kirk
authors.initials: K
authors.lastname: Rockett
authors.forename: Hassan
authors.initials: H
authors.lastname: Joof
authors.forename: Matthew
authors.initials: M
authors.lastname: Burton
authors.forename: David
authors.initials: D
authors.lastname: Mabey
authors.forename: Dominic
authors.initials: D
authors.lastname: Kwiatkowski
authors.forename: Robin
authors.initials: R
authors.lastname: Bailey
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D001766:Blindness / Q000209:etiology / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D002921:Cicatrix / Q000209:etiology / Q000235:genetics / Q000276:immunology; D004843:Epistasis, Genetic; D005260:Female; D005714:Gambia; D014644:Genetic Variation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014141:Trachoma / Q000150:complications / Q000235:genetics* / Q000276:immunology*; D055815:Young Adult
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020780:Matrix Metalloproteinase 9