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.

Immunopathogenesis of Progressive Scarring Trachoma: Results of a 4-Year Longitudinal Study in Tanzanian Children

“…The reason for its upregulation alongside IL23A in scarring progressors in response to C. trachomatis relative to expression in nonprogressors is unclear. A genome-wide association study of scarring trachoma suggested that host cell cycle, cell surface receptor signaling, and immune response pathways were associated with scarring, although no specific cytokine risk loci were identified (40).…”

Pathways-wide genetic risks in Chlamydial infections overlap between tissue tropisms: A genome-wide association scan

“…Whilst we are confident that the positive signals from the PRKG1 and NPSR1-AS1 region are interesting enough to warrant further study, we recognize that the false negative rate is very high. To leverage additional power from the small sample, we focused on pathways-wide analysis that was similar to the one used previously [14]. We determined that the ALIGATOR method was somewhat unstable with regards to the specific pathways that were highlighted at different thresholds of nominal significance (Supplementary Table 2).…”

“…Imputation was carried out as described previously [21,22] and included prephasing with Shapeit [23,24] (informed by HapMap Phase II, build 37) and post-imputation filtering for high quality imputed SNPs with IMPUTE2 info score > 0.8 and/or MAF > 0.01 [14,25]. Imputation was performed with IMPUTE2 [21,22] using the worldwide 1000 Genomes phase I data set of 1092 reference specimens [26].…”

“…The R package SNPath (linchen.fhcrc.org/grass.html) was used to run the Assignment List GO AnnotaTOR (ALIGATOR) algorithm [12] on 1345 Reactome pathways [18]. In order to make the results directly comparable to those of the previous study [14], we chose to use the same pathways list that was used in that analysis (www.reactome.org, accessed April 2013). The P values from EMMAX tests of association were sampled to remove SNPs that were > 20 kb away from any gene in a list of ~17,000 genes that were consistently cross-referenced between Entrez and Ensembl and for which a HUGO gene name had been assigned (http://www.gettinggeneticsdone.com/2011_06_01_archive.html).…”

“…In our recent discovery phase genome-wide association study (GWAS) [14] we found that a number of genes and molecular pathways were associated with TS. That study applied both a classical single nucleotide polymorphism (SNP) association and systems based analysis [15][16][17] that focussed on the cumulative effects of multiple SNPs in the context of well-defined and curated molecular pathways of protein-protein interactions [18].…”