Admixture Mapping of Staphylococcus Aureus Bacteremia

In this study, we used admixture mapping to test the hypothesis that genomic variations with different frequencies in European and African ancestral genomes influence susceptibility to Staphylococcus aureus bacteremia (SAB) in a sample of African Americans. A total of 565 adult African Americans were genotyped for admixture mapping. Cases were unique African American adult inpatients with monomicrobial SAB (N=390) and controls are age-matched adult African American inpatients with no current or past S. aureus infection (N=175). After empirical multiplicity adjustment, one region on chromosome 6 (52 SNPs, P = 4.56e-05) in the HLA class II region was found to exhibit a genome-wide statistically significant increase in European ancestry. This region encodes genes involved in HLA-mediated immune response and these results provide additional evidence for genetic variation influencing HLA-mediated immunity, modulating susceptibility to SAB. ]]>
In this study, we used admixture mapping to test the hypothesis that genomic variations with different frequencies in European and African ancestral genomes influence susceptibility to Staphylococcus aureus bacteremia in a sample of African Americans. A total of 565 adult African Americans were genotyped for admixture mapping. Cases were unique African American adult inpatients with monomicrobial SAB (N=390) and controls are age-matched adult African American inpatients with no current or past S. aureus infection (N=175).
After empirical multiplicity adjustment, one region on chromosome 6 (52 SNPs, P = 4.56e-05) in the HLA class II region was found to exhibit a genome-wide statistically significant increase in European ancestry. This region encodes genes involved in HLA-mediated immune response and these results provide additional evidence for genetic variation influencing HLA-mediated immunity, modulating susceptibility to SAB.
]]>Some of the samples for this study have been collected by our previous Duke IRB approved protocols Pro00008031 (formerly 602-00-8R1ER and 1048-00-6R2ER). Health Insurance Portability and Accountability Act (HIPAA) compliant procedures were used to collect both the bloodstream Staphylococcus aureus isolates as well as human blood specimens. A separate IRB protocol was amended/written to conduct this GWAS study (Duke eIRB #Pro00011097). Subjects enrolled under this protocol were consented to data sharing. Each subject was assigned a unique code, and the PI will not disclose the key that links this code to personal identifiers. Inclusion criteria for cases were as follows: Adults (≥ 18 years) with culture-confirmed bloodstream infection. Patients with bloodstream infection transferred to DUMC are eligible if pathogen speciation and antibiotic susceptibilities are confirmed by the DCML. Patient or patient's representative provides signed informed consent allowing participation, unless patient expires prior to notification of blood culture results. In this instance, human DNA samples, limited clinical data, and the bacterial isolate from the subject are catalogued using an IRB-approved Notification of Decedent Research. Exclusion criteria for cases were as follows: Prior enrollment of patient in this investigation (to ensure statistical independence of observations). Bloodstream infection that is not confirmed by culture and speciation at the DCML. Outpatient status. WGA profiles from Protocol ID # Pro00006745 (Title: "Whole Genome Analysis of Adverse Outcomes after Cardiac Surgery") were used as controls for the GWAS study. Control subjects screened included 950-1000 white persons undergoing Coronary Artery Bypass Graft surgery and previously consented and enrolled into Duke IRB#s Pro00003604 and Pro00003812. The subjects in these two protocols were used as control subjects in the study conducted under eIRB# Pro00011097. Access to the patients protected health information via the e-Browser was used to ascertain the absence of Staphylococcus aureus infections postoperatively. Subjects with a diagnosis of Staphylococcus aureus infections postoperatively were excluded as a control subjects. ]]>
Pre-publication versions of this article and author comments to reviewers are available by contacting [e-mail]. Original Submission 4/9/2013 Submitted Original manuscript Resubmission - Version 2 Submitted Manuscript version 2 5/24/2013 Reviewed Reviewer Report - Tianming Li 9/26/2013 Reviewed Reviewer Report - Ruth Massey 10/10/2013 Reviewed Reviewer Report - Catherine Stein 10/11/2013 Reviewed Reviewer Report - Dana Crawford 10/18/2013 Reviewed Reviewer Report - Marie-Anne Shaw 11/21/2013 Author responded Author comments - Charlotte Nelson Resubmission - Version 3 11/21/2013 Submitted Manuscript version 3 12/12/2013 Reviewed Reviewer Report - Marie-Anne Shaw 12/15/2013 Reviewed Reviewer Report - Tianming Li 12/19/2013 Reviewed Reviewer Report - Dana Crawford 1/22/2014 Author responded Author comments - Charlotte Nelson Resubmission - Version 4 1/22/2014 Submitted Manuscript version 4 Publishing 2/6/2014 Editorially accepted 2/13/2014 Article published PMID:24524581 ]]>