Human Genetic Susceptibility to Native Valve Staphylococcus aureus Endocarditis in Patients With S. aureus Bacteremia: Genome-Wide Association Study

Karen Moreau,Xavier Duval,Alex Van Belkum,Yohan Bossé,Cofrasa Study Groups ,Alisson Clemenceau,The French Virsta-Aepei ,Marie L Erpelding,Robert L Skov,Florence Couzon,Coralie Bouchiat,Francois Vandenesch,David Messika-Zeitoun,The Danish Dansab Study Group ,Paal S Andersen,Vincent Le Moing,Niels E Bruun

doi:10.3389/fmicb.2018.00640

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.

Highlights

Staphylococcus aureus is the second most frequent pathogen causing bloodstream infection with an average rate of 25 per 100,000 individuals per year in North America and western European countries (Laupland, 2013)
Among the 2,091 patients enrolled in the VIRSTA cohort study (Le Moing et al, 2015), 156 patients fulfilled the inclusion criteria for the case control study, gave consent and were genotyped by single nucleotide polymorphisms (SNPs) microarray (Figure 1)
By analyzing the S. aureus isolates from the VIRSTA cohort, we recently demonstrated that the strains of S. aureus associated with endocarditis were genotypically distinct from those responsible for uncomplicated bacteremia (Bouchiat et al, 2015)

Summary

Introduction

Staphylococcus aureus is the second most frequent pathogen causing bloodstream infection with an average rate of 25 per 100,000 individuals per year in North America and western European countries (Laupland, 2013). IE is still a rare but severe disease, with a mortality of approximately 20% [10–30%] during the initial hospitalization phase (Moreillon and Que, 2004; Murdoch et al, 2009; Hoen and Duval, 2012), and up to 40% at a 5 year endpoint (Bannay et al, 2011). Regarding host-related factors in the context of SAB, underlying diseases such as diabetes, HIV infection, hemodialysis and intravenous drug use have been shown to be primary SaIE risk factors (Li and Somerville, 1998; Cabell et al, 2002; Chang et al, 2003; Miro et al, 2005; Gebo et al, 2006; Habib et al, 2009; Hoen and Duval, 2012). Note that 30–50% of SaIE occurs without any obvious involvement of the classical host risk factors, suggesting that additional host genetic factors may be involved (Hoen and Duval, 2012; Le Moing et al, 2015)

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Discussion

Conclusion