Abstract
BackgroundTrachoma, 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.MethodsLinkage 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.ResultsLD 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.Conclusioninnate immune response SNP-haplotypes are linked to ocular Ct sequelae. This work illustrates the first example of epistatic effects of two genes on trachoma.
Highlights
Trachoma, a chronic keratoconjunctivitis caused by Chlamydia trachomatis, is the world's commonest infectious cause of blindness
Epistasis The simplest system of two interacting loci using conditional logistic regression was used to assess epistasis between MMP9Q279R genotypes, which we previously reported as conferring risk to scarring trachoma and trichiasis, and genotypes at the unlinked interleukin 8 (IL8) and CSF2 loci
By means of combining Linkage disequilibrium (LD) mapping, case-control and epistatic analyses we have identified a genetic association between severe outcome of ocular Chlamydia trachomatis (Ct) infection and the pro-inflammatory genes IL8 and CSF2 within the chemokine and cytokine gene clusters in chromosomes 4q and 5q31 respectively
Summary
A chronic keratoconjunctivitis caused by Chlamydia trachomatis, is the world's commonest infectious cause of blindness. Ocular Chlamydia trachomatis (Ct) infection causes inflammatory changes in the conjunctiva, and repeated infections sometimes lead to fibrosis and scarring of the sub tarsal conjunctiva. This may cause the upper eyelid margin to turn inwards so that the lashes rub against the eyeball (trichiasis), which damages the cornea and leads to blindness [3]. Some individuals develop severe and persistent clinical disease in response to infection [4,5], and are more likely to develop conjunctival scarring and trichiasis in later life [6] The reasons for this heterogeneity in susceptibility to chlamydial infection and disease progression following a rather uniform bacterial exposure remain incompletely understood; the host genetic background may account for part of the risk. Identification of genetic loci which contribute to the burden of trachoma sequelae in the population may help to dissect the immunopathology of ocular Ct infection in humans
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