Genome wide association study of SNP-, gene-, and pathway-based approaches to identify genes influencing susceptibility to Staphylococcus aureus infections.
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 (p gene = 1.20E-05), which codes an integrin binding molecule (focal adhesion), and DAPK3 (p gene = 5.10E-05), a serine/threonine kinase (apoptosis and cytokinesis). The pathway analyses identified epithelial cell responses to mechanical and non-mechanical stress.


CONCLUSIONS
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.
Biomedical Informatics Research Center, Marshfield Clinic Research Foundation Marshfield, WI, USA.
Zhan
Z
Ye
Center for Human Genetics, Marshfield Clinic Research Foundation Marshfield, WI, USA.
Daniel A
DA
Vasco
Center for Human Genetics, Marshfield Clinic Research Foundation Marshfield, WI, USA.
Tonia C
TC
Carter
Center for Human Genetics, Marshfield Clinic Research Foundation Marshfield, WI, USA.
Murray H
MH
Brilliant
Center for Human Genetics, Marshfield Clinic Research Foundation Marshfield, WI, USA.
Steven J
SJ
Schrodi
Center for Human Genetics, Marshfield Clinic Research Foundation Marshfield, WI, USA.
Sanjay K
SK
Shukla
GWAS; Staphylococcus aureus; disease susceptibility; integrin and keratin disease pathway; skin and soft tissue infection