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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

Results of GWAS Analysis using EMMAX.(A) QQ plot: There is genome-wide deflation(λ = 0.982SE = 1.74e−05) of thetest statistic when the phenotype is corrected for kinship only. (B)QQ plot: Phenotype correction for age, gender and pairwise kinship removedany deviation from the  expectation of the genome-wide test statistic(λ = 1.001,SE = 8.7e−7).(C) Manhattan plot showing index SNPs withPEMMAX < 5 × 10−6.
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f1: Results of GWAS Analysis using EMMAX.(A) QQ plot: There is genome-wide deflation(λ = 0.982SE = 1.74e−05) of thetest statistic when the phenotype is corrected for kinship only. (B)QQ plot: Phenotype correction for age, gender and pairwise kinship removedany deviation from the expectation of the genome-wide test statistic(λ = 1.001,SE = 8.7e−7).(C) Manhattan plot showing index SNPs withPEMMAX < 5 × 10−6.

Mentions: The case and control groups were approximately equivalent with respect to genderand ethnicity. 70% of cases and 63% of controls were female. Self-describedethnic composition of the cases was 29% Jola, 27% Mandinka, 21% Wolof, 10% Fulaand 13% other/no data. In controls the composition was 25% Jola, 24% Mandinka,21% Wolof, 8% Fula and 22% other/no data. Median age was 49 (range32–60) in cases and 37 (range 12–52) in controls(t = −3.6019,P = 0.0003). First pass tests of association in EMMAXled to genome-wide deflation of the test statistics(λ = 0.982SE = 1.74e−05) (Fig 1A) that could be directly attributed to the differingage and gender distributions between cases and controls. Modelling the phenotypeto adjust for age and gender successfully controlled for this and no genome-widedeviation from the was subsequently observed(λ = 1.001,SE = 8.7 × 10−7)(Fig. 1B). Neither principal components analysis (PCA)(Supplementary Figures 3 &4), nor tests of proportional identity by state (IBS) variance inPLINK identified significant levels of within or between group geneticvariance.


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)

Results of GWAS Analysis using EMMAX.(A) QQ plot: There is genome-wide deflation(λ = 0.982SE = 1.74e−05) of thetest statistic when the phenotype is corrected for kinship only. (B)QQ plot: Phenotype correction for age, gender and pairwise kinship removedany deviation from the  expectation of the genome-wide test statistic(λ = 1.001,SE = 8.7e−7).(C) Manhattan plot showing index SNPs withPEMMAX < 5 × 10−6.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Results of GWAS Analysis using EMMAX.(A) QQ plot: There is genome-wide deflation(λ = 0.982SE = 1.74e−05) of thetest statistic when the phenotype is corrected for kinship only. (B)QQ plot: Phenotype correction for age, gender and pairwise kinship removedany deviation from the expectation of the genome-wide test statistic(λ = 1.001,SE = 8.7e−7).(C) Manhattan plot showing index SNPs withPEMMAX < 5 × 10−6.
Mentions: The case and control groups were approximately equivalent with respect to genderand ethnicity. 70% of cases and 63% of controls were female. Self-describedethnic composition of the cases was 29% Jola, 27% Mandinka, 21% Wolof, 10% Fulaand 13% other/no data. In controls the composition was 25% Jola, 24% Mandinka,21% Wolof, 8% Fula and 22% other/no data. Median age was 49 (range32–60) in cases and 37 (range 12–52) in controls(t = −3.6019,P = 0.0003). First pass tests of association in EMMAXled to genome-wide deflation of the test statistics(λ = 0.982SE = 1.74e−05) (Fig 1A) that could be directly attributed to the differingage and gender distributions between cases and controls. Modelling the phenotypeto adjust for age and gender successfully controlled for this and no genome-widedeviation from the was subsequently observed(λ = 1.001,SE = 8.7 × 10−7)(Fig. 1B). Neither principal components analysis (PCA)(Supplementary Figures 3 &4), nor tests of proportional identity by state (IBS) variance inPLINK identified significant levels of within or between group geneticvariance.

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