Abstract
Background: We conducted a genome-wide association study (GWAS) to identify specific genetic variants that underlie susceptibility to diseases caused by Staphylococcus aureus in humans.Methods: Cases (n = 309) and controls (n = 2925) were genotyped at 508,921 single nucleotide polymorphisms (SNPs). Cases had at least one laboratory and clinician confirmed disease caused by S. aureus whereas controls did not. R-package (for SNP association), EIGENSOFT (to estimate and adjust for population stratification) and gene- (VEGAS) and pathway-based (DAVID, PANTHER, and Ingenuity Pathway Analysis) analyses were performed.Results: No SNP reached genome-wide significance. Four SNPs exceeded the p < 10−5 threshold including two (rs2455012 and rs7152530) reaching a p-value < 10−7. The nearby genes were PDE4B (rs2455012), TXNRD2 (rs3804047), VRK1 and BCL11B (rs7152530), and PNPLA5 (rs470093). The top two findings from the gene-based analysis were NMRK2 (pgene = 1.20E-05), which codes an integrin binding molecule (focal adhesion), and DAPK3 (pgene = 5.10E-05), a serine/threonine kinase (apoptosis and cytokinesis). The pathway analyses identified epithelial cell responses to mechanical and non-mechanical stress.Conclusion: We identified potential susceptibility genes for S. aureus diseases in this preliminary study but confirmation by other studies is needed. The observed associations could be relevant given the complexity of S. aureus as a pathogen and its ability to exploit multiple biological pathways to cause infections in humans.
Highlights
Staphylococcus aureus is a complex human pathogen due to its ability to survive both as a carriage organism, and behave as an opportunistic pathogen in a susceptible host
The observed associations could be relevant given the complexity of S. aureus as a pathogen and its ability to exploit multiple biological pathways to cause infections in humans
Genetic susceptibility to S. aureus infections is expected to be complex because this pathogen uses a wide variety of virulence factors that interact with several host pathways to cause disease in humans
Summary
Staphylococcus aureus is a complex human pathogen due to its ability to survive both as a carriage organism, and behave as an opportunistic pathogen in a susceptible host. It is a leading cause of invasive bacterial infection that contributes to substantial morbidity and mortality worldwide. This bacterium can cause a variety of diseases ranging from mild to severe skin and soft tissue infections, keratitis, and osteomyelitis to life-threatening bacteremia, pneumonia, endocarditis, and sepsis (Lowy, 1998; Rehm, 2008). Genetic susceptibility to S. aureus infections is expected to be complex because this pathogen uses a wide variety of virulence factors that interact with several host pathways to cause disease in humans. We conducted a genome-wide association study (GWAS) to identify specific genetic variants that underlie susceptibility to diseases caused by Staphylococcus aureus in humans
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