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Conjunctival fibrosis and the innate barriers to Chlamydia trachomatis intracellular infection: a genome wide association study.

Roberts Ch, Franklin CS, Makalo P, Joof H, Sarr I, Mahdi OS, Sillah A, Bah M, Payne F, Jeffreys AE, Bottomley W, Natividad A, Molina-Gonzalez S, Burr SE, Preston M, Kwiatkowski D, Rockett KA, Clark TG, Burton MJ, Mabey DC, Bailey R, Barroso I, Holland MJ - Sci Rep (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: London School of Hygiene and Tropical Medicine, London, UK.

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.

No MeSH data available.


Related in: MedlinePlus

Regional Plot of the most significant index SNP region (rs111513399,PREX2).Window size 250 kb. LD with index SNP (R2 value) is indicatedby colour. LD structure was generated from the GWAS data after imputation.The most significant PREX2 region coincides with a common splicevariation. Known transcript variants (A: NP_079146.2 and B: NP_079446.3) areindicated by horizontal red lines and exons are indicated by crosshatchingverticals.
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f2: Regional Plot of the most significant index SNP region (rs111513399,PREX2).Window size 250 kb. LD with index SNP (R2 value) is indicatedby colour. LD structure was generated from the GWAS data after imputation.The most significant PREX2 region coincides with a common splicevariation. Known transcript variants (A: NP_079146.2 and B: NP_079446.3) areindicated by horizontal red lines and exons are indicated by crosshatchingverticals.

Mentions: Twenty-seven genomic regions were identified by an index SNP withPEMMAX < 5 × 10−6(Fig. 1B, Supplementary Table 1), although none achieved genome-widesignificance(PEMMAX < 5 × 10−8).Twelve index SNPs (Table 1 and Supplementary Figure 6) had at least onesupporting SNP (either directly genotyped or imputed) in the region that was inhigh LD (r2 > 0.6) with the index.Five of these were located within non-coding regions of genes includingPREX2 (rs111513399), CTNND (rs28731189), PHYH(rs11258313), NSUN6 (rs201134023) and USP6 (rs9895748). The mostsignificant SNP (rs111513399) was in high LD with a number of SNPs withPEMMAX < 1 × 10−5and was located in close proximity to the site of a common splice variation ofunknown biological relevance in PREX2 (Fig. 2).


Conjunctival fibrosis and the innate barriers to Chlamydia trachomatis intracellular infection: a genome wide association study.

Roberts Ch, Franklin CS, Makalo P, Joof H, Sarr I, Mahdi OS, Sillah A, Bah M, Payne F, Jeffreys AE, Bottomley W, Natividad A, Molina-Gonzalez S, Burr SE, Preston M, Kwiatkowski D, Rockett KA, Clark TG, Burton MJ, Mabey DC, Bailey R, Barroso I, Holland MJ - Sci Rep (2015)

Regional Plot of the most significant index SNP region (rs111513399,PREX2).Window size 250 kb. LD with index SNP (R2 value) is indicatedby colour. LD structure was generated from the GWAS data after imputation.The most significant PREX2 region coincides with a common splicevariation. Known transcript variants (A: NP_079146.2 and B: NP_079446.3) areindicated by horizontal red lines and exons are indicated by crosshatchingverticals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663496&req=5

f2: Regional Plot of the most significant index SNP region (rs111513399,PREX2).Window size 250 kb. LD with index SNP (R2 value) is indicatedby colour. LD structure was generated from the GWAS data after imputation.The most significant PREX2 region coincides with a common splicevariation. Known transcript variants (A: NP_079146.2 and B: NP_079446.3) areindicated by horizontal red lines and exons are indicated by crosshatchingverticals.
Mentions: Twenty-seven genomic regions were identified by an index SNP withPEMMAX < 5 × 10−6(Fig. 1B, Supplementary Table 1), although none achieved genome-widesignificance(PEMMAX < 5 × 10−8).Twelve index SNPs (Table 1 and Supplementary Figure 6) had at least onesupporting SNP (either directly genotyped or imputed) in the region that was inhigh LD (r2 > 0.6) with the index.Five of these were located within non-coding regions of genes includingPREX2 (rs111513399), CTNND (rs28731189), PHYH(rs11258313), NSUN6 (rs201134023) and USP6 (rs9895748). The mostsignificant SNP (rs111513399) was in high LD with a number of SNPs withPEMMAX < 1 × 10−5and was located in close proximity to the site of a common splice variation ofunknown biological relevance in PREX2 (Fig. 2).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: London School of Hygiene and Tropical Medicine, London, UK.

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.

No MeSH data available.


Related in: MedlinePlus