A genome-wide association study of variants associated with acquisition of Staphylococcus aureus bacteremia in a healthcare setting

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Abstract

Background

Humans vary in their susceptibility to acquiring Staphylococcus aureus infection, and research suggests that there is a genetic basis for this variability. Several recent genome-wide association studies (GWAS) have identified variants that may affect susceptibility to infectious diseases, demonstrating the potential value of GWAS in this arena.

Methods

We conducted a GWAS to identify common variants associated with acquisition of S. aureus bacteremia (SAB) resulting from healthcare contact. We performed a logistic regression analysis to compare patients with healthcare contact who developed SAB (361 cases) to patients with healthcare contact in the same hospital who did not develop SAB (699 controls), testing 542,410 SNPs and adjusting for age (by decade), sex, and 6 significant principal components from our EIGENSTRAT analysis. Additionally, we evaluated the joint effect of the host and pathogen genomes in association with severity of SAB infection via logistic regression, including an interaction of host SNP with bacterial genotype, and adjusting for age (by decade), sex, the 6 significant principal components, and dialysis status. Bonferroni corrections were applied in both analyses to control for multiple comparisons.

Results

Ours is the first study that has attempted to evaluate the entire human genome for variants potentially involved in the acquisition or severity of SAB. Although this study identified no common variant of large effect size to have genome-wide significance for association with either the risk of acquiring SAB or severity of SAB, the variant (rs2043436) most significantly associated with severity of infection is located in a biologically plausible candidate gene ( CDON, a member of the immunoglobulin family) and may warrant further study.

Conclusions

The genetic architecture underlying SAB is likely to be complex. Future investigations using larger samples, narrowed phenotypes, and advances in both genotyping and analytical methodologies will be important tools for identifying causative variants for this common and serious cause of healthcare-associated infection.

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Most cited references 23

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Invasive methicillin-resistant Staphylococcus aureus infections in the United States.

R. Monina Klevens, Melissa Morrison, Joelle Nadle … (2007)

As the epidemiology of infections with methicillin-resistant Staphylococcus aureus (MRSA) changes, accurate information on the scope and magnitude of MRSA infections in the US population is needed. To describe the incidence and distribution of invasive MRSA disease in 9 US communities and to estimate the burden of invasive MRSA infections in the United States in 2005. Active, population-based surveillance for invasive MRSA in 9 sites participating in the Active Bacterial Core surveillance (ABCs)/Emerging Infections Program Network from July 2004 through December 2005. Reports of MRSA were investigated and classified as either health care-associated (either hospital-onset or community-onset) or community-associated (patients without established health care risk factors for MRSA). Incidence rates and estimated number of invasive MRSA infections and in-hospital deaths among patients with MRSA in the United States in 2005; interval estimates of incidence excluding 1 site that appeared to be an outlier with the highest incidence; molecular characterization of infecting strains. There were 8987 observed cases of invasive MRSA reported during the surveillance period. Most MRSA infections were health care-associated: 5250 (58.4%) were community-onset infections, 2389 (26.6%) were hospital-onset infections; 1234 (13.7%) were community-associated infections, and 114 (1.3%) could not be classified. In 2005, the standardized incidence rate of invasive MRSA was 31.8 per 100,000 (interval estimate, 24.4-35.2). Incidence rates were highest among persons 65 years and older (127.7 per 100,000; interval estimate, 92.6-156.9), blacks (66.5 per 100,000; interval estimate, 43.5-63.1), and males (37.5 per 100,000; interval estimate, 26.8-39.5). There were 1598 in-hospital deaths among patients with MRSA infection during the surveillance period. In 2005, the standardized mortality rate was 6.3 per 100,000 (interval estimate, 3.3-7.5). Molecular testing identified strains historically associated with community-associated disease outbreaks recovered from cultures in both hospital-onset and community-onset health care-associated infections in all surveillance areas. Invasive MRSA infection affects certain populations disproportionately. It is a major public health problem primarily related to health care but no longer confined to intensive care units, acute care hospitals, or any health care institution.

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eBURST: inferring patterns of evolutionary descent among clusters of related bacterial genotypes from multilocus sequence typing data.

E Feil, B. C. Li, D M Aanensen … (2004)

The introduction of multilocus sequence typing (MLST) for the precise characterization of isolates of bacterial pathogens has had a marked impact on both routine epidemiological surveillance and microbial population biology. In both fields, a key prerequisite for exploiting this resource is the ability to discern the relatedness and patterns of evolutionary descent among isolates with similar genotypes. Traditional clustering techniques, such as dendrograms, provide a very poor representation of recent evolutionary events, as they attempt to reconstruct relationships in the absence of a realistic model of the way in which bacterial clones emerge and diversify to form clonal complexes. An increasingly popular approach, called BURST, has been used as an alternative, but present implementations are unable to cope with very large data sets and offer crude graphical outputs. Here we present a new implementation of this algorithm, eBURST, which divides an MLST data set of any size into groups of related isolates and clonal complexes, predicts the founding (ancestral) genotype of each clonal complex, and computes the bootstrap support for the assignment. The most parsimonious patterns of descent of all isolates in each clonal complex from the predicted founder(s) are then displayed. The advantages of eBURST for exploring patterns of evolutionary descent are demonstrated with a number of examples, including the simple Spain(23F)-1 clonal complex of Streptococcus pneumoniae, "population snapshots" of the entire S. pneumoniae and Staphylococcus aureus MLST databases, and the more complicated clonal complexes observed for Campylobacter jejuni and Neisseria meningitidis.

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Health care--associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections.

N. Friedman, Keith S. Kaye, Jason Stout … (2002)

Bloodstream infections occurring in persons residing in the community, regardless of whether those persons have been receiving health care in an outpatient facility, have traditionally been categorized as community-acquired infections. To develop a new classification scheme for bloodstream infections that distinguishes among community-acquired, health care-associated, and nosocomial infections. Prospective observational study. One academic medical center and two community hospitals. All adult patients admitted to the hospital with bloodstream infection. Demographic characteristics, living arrangements before hospitalization, comorbid medical conditions, factors predisposing to bloodstream infection, date of hospitalization, dates and number of positive blood cultures, results of microbiological susceptibility testing, dates of hospital discharge or death, and mortality rates at 3 to 6 months of follow-up. 504 patients with bloodstream infections were enrolled; 143 (28%) had community-acquired bloodstream infections, 186 (37%) had health care-associated bloodstream infections, and 175 (35%) had nosocomial bloodstream infections. Of the 186 patients with health care-associated bloodstream infection, 29 resided in a nursing home, 64 were receiving home health care, 78 were receiving intravenous or intravascular therapy at home or in a clinic, and 117 had been hospitalized in the 90 days before their bloodstream infection. Cancer was more common in patients with health care-associated or nosocomial bloodstream infection than in patients with community-acquired bloodstream infection. Intravascular devices were the most common source of health care-associated and nosocomial infections, and Staphylococcus aureus was the most frequent pathogen in these types of infections. Methicillin-resistant S. aureus occurred with similar frequency in the groups with health care-associated infection (52%) and nosocomial infection (61%) but was uncommon in the group with community-acquired bloodstream infection (14%) (P = 0.001). Mortality rate at follow-up was greater in patients with health care-associated infection (29% versus 16%; P = 0.019) or nosocomial infection (37% versus 16%; P < 0.001) than in patients with community-acquired infection. Health care-associated bloodstream infections are similar to nosocomial infections in terms of frequency of various comorbid conditions, source of infection, pathogens and their susceptibility patterns, and mortality rate at follow-up. A separate category for health care-associated bloodstream infections is justified, and this new category will have obvious implications for choices about empirical therapy and infection-control surveillance.

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Author and article information

Journal

Journal ID (nlm-ta): BMC Infect Dis

Journal ID (iso-abbrev): BMC Infect. Dis

Title: BMC Infectious Diseases

Publisher: BioMed Central

ISSN (Electronic): 1471-2334

Publication date Collection: 2014

Publication date (Electronic): 13 February 2014

Volume: 14

Page: 83

Affiliations

[1 ]Duke Clinical Research Institute, Duke University Medical Center, 2400 Pratt Street, Room 0311 Terrace Level, Durham, NC 27705, USA

[2 ]Center for Human Genome Variation, Duke University School of Medicine, Durham, NC 27708, USA

[3 ]Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA

[4 ]Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA

[5 ]Department of Human Genetics and Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL 33136, USA

[6 ]Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA

[7 ]UT Southwestern Medical Center, Dallas, TX 75390, USA

Article

Publisher ID: 1471-2334-14-83

DOI: 10.1186/1471-2334-14-83

PMC ID: 3928605

PubMed ID: 24524581

SO-VID: 6bd5b084-9bbf-4516-a0b8-50f361f8a3d9

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

A genome-wide association study of variants associated with acquisition of Staphylococcus aureus bacteremia in a healthcare setting

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Abstract

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Most cited references 23

Invasive methicillin-resistant Staphylococcus aureus infections in the United States.

eBURST: inferring patterns of evolutionary descent among clusters of related bacterial genotypes from multilocus sequence typing data.

Health care--associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections.

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