Human genetic susceptibility to native valve Staphylococcus aureus endocarditis in patients with S. aureus bacteremia: Genome-wide association study

Karen Moreau*, Alisson Clemenceau, The French VIRSTA-AEPEI, COFRASA Study Groups and the Danish DANSAB Study Group, Vincent Le Moing, David Messika-Zeitoun, Paal S. Andersen, Niels E. Bruun, Robert L. Skov, Florence Couzon, Coralie Bouchiat, Marie L. Erpelding, Alex van Belkum, Yohan Bossé, Xavier Duval, François Vandenesch

*Corresponding author for this work

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Abstract

Staphylococcus aureus infective endocarditis (SaIE) is a severe complication of S. aureus bacteremia (SAB) occurring in up to 22% of patients. Bacterial genetic factors and host conditions for SaIE have been intensely studied before; however, to date no study has focused on predisposing host genetic factors to SaIE. The present study aimed to identify genetic polymorphisms associated with SaIE by a Genome-Wide Association Study (GWAS) of 67 patients with definite native valve SaIE (cases) and 72 matched native valve patients with SAB but without IE (controls). All patients were enrolled in the VIRSTA cohort (Le Moing et al., 2015) study. Four single nucleotide polymorphisms (SNPs) located on chromosome 3 were associated with SaIE (P < 1 × 10-5) without reaching conventional genome-wide significance. For all, the frequency of the minor allele was lower in cases than in controls, suggesting a protective effect of the minor allele against SaIE. The same association was observed using an independent Danish verification cohort of SAB with (n = 57) and without (n = 123) IE. Ex vivo analysis of aortic valve tissues revealed that SaIE associated SNPs mentioned above were associated with significantly higher mRNA expression levels of SLC7A14, a predicted cationic amino acid transporter protein. Taken together, our results suggest an IE-protective effect of SNPs on chromosome 3 during the course of SAB. The effects of protective minor alleles may be mediated by increasing expression levels of SLC7A14 in valve tissues. We conclude that occurrence of SaIE may be the combination of a well-adapted bacterial genotype to a susceptible host.

Original languageEnglish
Article number640
JournalFrontiers in Microbiology
Volume9
Issue numberAPR
DOIs
Publication statusPublished - 4 Apr 2018

Bibliographical note

FUNDING:
The VIRSTA study (EUCRACT 2, 008-A00680-55) was funded
by the French Ministry of Health (Program Hospitalier de
Recherche Clinique 2008). The French national network on
IE/AEPEI which participated in the study is supported by
the Institut National de la Santé et de la Recherche Médicale
(INSERM). The study at Laval University was supported by
the Heart and Stroke Foundation of Canada, the Institut
Universitaire de Cardiologie et de Pneumologie de Québec
(IUCPQ) Foundation, and the Canadian Institutes of Health
Research grants (MOP102481 and MOP137058). YB holds
a Canada Research Chair in Genomics of Heart and Lung
Diseases. AC is the recipient of a doctoral studentship from the
“Centre de Recherche Institut Universitaire de Cardiologie et
de Pneumologie de Québec.” The COFRASA/GENERAC cohort
(clinicalTrial.gov number NCT 00338676 and NCT00647088)
was supported by grants from the Assistance Publique –
Hôpitaux de Paris (PHRC National 2005 and 2010, and PHRC
regional 2007).



Publisher Copyright:
© 2018 Moreau, Clemenceau, Le Moing, Messika-Zeitoun, Andersen, Bruun, Skov, Couzon, Bouchiat, Erpelding, van Belkum, Bossé, Duval, Vandenesch, the French VIRSTA-AEPEI, COFRASA Study Groups and the Danish DANSAB Study Group.

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