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.

Human genetic variation in GLS2 is associated with development of complicated Staphylococcus aureus bacteremia

“…Also, while there is previous association of the L581P variant (rs2657879) with plasma glutamine concentration, a biological mechanism for this association has yet to be elucidated. Finally, this study did not detect association with other loci previously associated with endocarditis ( SLC7A14 [ 38 ], in a study that included a subset of the Danish sample used here in the non-significant replication), with risk of SAB (HLA class II region [ 6 ]), or with biologically plausible candidate genes identified from prior human and mouse studies ( DUSP3 , FGA , FGB , FGG , FN1 , PSME3 , SPINK5 , TNFAIP8) . This is not surprising, as most of these genes (SLC7A14 being the exception) were associated with SAB overall, rather than complicated SAB in particular.…”

Polymorphism of protein genes associated with endothelial function in patients with infective endocarditis

“…Помимо причин, описанных выше, существует вероятность, что при выборе полиморфных сайтов для исследования мы упустили более значимый сайт, но до нашего исследования, насколько нам известно, подобных поисков генетических полиморфизмов не производилось. Результаты же первого исследования GWAS по связи генной изменчивости с ИЭ опубликованы совсем недавно -в апреле 2018г [21]. Авторы изучали потенциальную генетическую предрасположенность к развитию ИЭ в случае бактериемии S. aureus.…”

Infective Endocarditis: Inflammatory Response, Genetic Susceptibility, Oxidative Stress, and Multiple Organ Failure

“…Moreau et al [66] conducted a GWAS of 67 patients with definite native valve S. aureus IE (cases) and 72 matched native valve patients with S. aureus bacteremia but without IE (controls). Unfortunately, no SNPs were significantly associated with S. aureus IE at the genome-wide level (p < 5 Â 10 À8 ).…”