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

Karen Moreau; Alisson Clemenceau; 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; The French VIRSTA-AEPEI, COFRASA Study Groups and the Danish DANSAB Study Group; Helle Krogh Johansen; Christian Hassager; Henrik Ullum

doi:10.3389/fmicb.2018.00640

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

Karen Moreau^*, Alisson Clemenceau, 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, The French VIRSTA-AEPEI, COFRASA Study Groups and the Danish DANSAB Study Group, Helle Krogh Johansen, Christian Hassager, Henrik Ullum

^*Corresponding author for this work

Department of Clinical Medicine

8 Citations (Scopus)

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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 language	English
Article number	640
Journal	Frontiers in Microbiology
Volume	9
Pages (from-to)	1-11
ISSN	1664-302X
DOIs	https://doi.org/10.3389/fmicb.2018.00640
Publication status	Published - 4 Apr 2018

Keywords

Bacteremia
GWAS
Infectious endocarditis
SLC7A14
Staphylococcus aureus

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Human Genetic Susceptibility to Native Valve Staphylococcus aureus Endocarditis in Patients With S. aureus BacteremiaFinal published version, 1.57 MBLicence: CC BY

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Moreau, K., Clemenceau, A., Le Moing, V., Messika-Zeitoun, D., Andersen, P. S., Bruun, N. E., Skov, R. L., Couzon, F., Bouchiat, C., Erpelding, M. L., van Belkum, A., Bossé, Y., Duval, X., Vandenesch, F., The French VIRSTA-AEPEI, COFRASA Study Groups and the Danish DANSAB Study Group, Johansen, H. K., Hassager, C., & Ullum, H. (2018). Human Genetic Susceptibility to Native Valve Staphylococcus aureus Endocarditis in Patients With S. aureus Bacteremia: Genome-Wide Association Study. Frontiers in Microbiology, 9, 1-11. Article 640. https://doi.org/10.3389/fmicb.2018.00640

Moreau, K, Clemenceau, A, Le Moing, V, Messika-Zeitoun, D, Andersen, PS, Bruun, NE, Skov, RL, Couzon, F, Bouchiat, C, Erpelding, ML, van Belkum, A, Bossé, Y, Duval, X, Vandenesch, F, The French VIRSTA-AEPEI, COFRASA Study Groups and the Danish DANSAB Study Group, Johansen, HK , Hassager, C & Ullum, H 2018, 'Human Genetic Susceptibility to Native Valve Staphylococcus aureus Endocarditis in Patients With S. aureus Bacteremia: Genome-Wide Association Study', Frontiers in Microbiology, vol. 9, 640, pp. 1-11. https://doi.org/10.3389/fmicb.2018.00640

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

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.",

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author = "Karen Moreau and Alisson Clemenceau and {Le Moing}, Vincent and David Messika-Zeitoun and Andersen, {Paal S.} and Bruun, {Niels E.} and Skov, {Robert L.} and Florence Couzon and Coralie Bouchiat and Erpelding, {Marie L.} and {van Belkum}, Alex and Yohan Boss{\'e} and Xavier Duval and Fran{\c c}ois Vandenesch and {The French VIRSTA-AEPEI, COFRASA Study Groups and the Danish DANSAB Study Group} and Johansen, {Helle Krogh} and Christian Hassager and Henrik Ullum",

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T2 - Genome-Wide Association Study

AU - Moreau, Karen

AU - Clemenceau, Alisson

AU - Le Moing, Vincent

AU - Messika-Zeitoun, David

AU - Andersen, Paal S.

AU - Bruun, Niels E.

AU - Skov, Robert L.

AU - Couzon, Florence

AU - Bouchiat, Coralie

AU - Erpelding, Marie L.

AU - van Belkum, Alex

AU - Bossé, Yohan

AU - Duval, Xavier

AU - Vandenesch, François

AU - The French VIRSTA-AEPEI, COFRASA Study Groups and the Danish DANSAB Study Group

AU - Johansen, Helle Krogh

AU - Hassager, Christian

AU - Ullum, Henrik

PY - 2018/4/4

Y1 - 2018/4/4

N2 - 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.

AB - 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.

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KW - Infectious endocarditis

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JO - Frontiers in Microbiology

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ER -

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

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Keywords

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