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.
Highlights
Since the trachomatous scarring (TS) phenotype can be readily observed in the field using a magnifying loupe, trachoma represents an ideal platform for the study of genetic and biological factors that modulate the pathophysiological response to human Chlamydia trachomatis (Ct) infections
Few genome-wide associations were reported in several large-scale GWAS20–22 and this could be attributed to the reduced power of the studies which resulted from the increased genetic diversity, complex population structures and the low degree of linkage disequilibrium (LD) in the studied populations[23]
First pass tests of association in EMMAX led to genome-wide deflation of the test statistics (λ = 0.982 SE = 1.74e−05) (Fig 1A) that could be directly attributed to the differing age and gender distributions between cases and controls
Summary
Not all individuals who become infected with Ct (either through STI or in the eye) will suffer clinically significant levels of disease Those who suffer repeated inflammatory episodes at the conjunctiva have been identified as being at high risk of progressing to TS8 and a increased risk of genitourinary tract pathology has been linked to repeated Ct STIs6. Recent developments in pathways based analysis of GWAS data enable more extensive, multi-SNP analysis and the collapsing of information across networks of functionally interacting polymorphisms[24,25,26,27]. This may add substantially to the discovery power of GWAS in complex phenotypes such as infectious diseases[28]. We sought to support the GWAS pathway level analysis features by performing a pathways level analysis on Gene Expression Omnibus (GEO) deposited trachoma data-sets from The Gambia, Tanzania and Ethiopia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
