162 Chapter 8 Host genetic variation and SAB Genetic risk factors for infection have been identified in a wide range of infectious diseases [29]. A landmark study performed in the 1980s determined children of adults who experienced premature death due to infection were more likely to experience death due to infection themselves, suggesting a heritable basis for their infection risk [30]. Rare primary immunodeficiency syndromes such as chronic granulomatous disease, hyper-IgE syndrome, and Chédiak–Higashi have been associated with increased susceptibility to S. aureus infection [31–34]. Few studies have examined the genetic risk factors for S. aureus bloodstream infections and even less focus on persistent MRSAB. A fascinating study by Oestergaard et al. was performed in 2016 by examining a database consisting of almost all parents and children born in Denmark between 1954 and 2016 (n = 8,951,393) [35]. On the basis of 18,626 reported cases of SAB and 34,774 first-degree relatives, the investigators found that first-degree relatives of patients hospitalized for SAB were more likely to experience an episode of SAB themselves (standardized incidence ratio (SIR) of 2.49; 95% confidence interval (CI) 1.95–3.19). The risk was particularly notable in siblings of patients with SAB (SIR, 5.01; 95% CI 3.30–7.62) compared to parents (SIR, 1.96; 95% CI 1.45–2.67). While these data provide compelling evidence for heritable risk factors for acquiring SAB, the specific genetic defect remains unknown. Three genome-wide association studies (GWAS) have been performed to identify host genetic variability that can predispose to SAB. Two smaller studies by Nelson et al. (361 SAB cases and 699 controls) and Ye et al. (309 cases and 2925 controls) did not identify single-nucleotide polymorphisms (SNPs) with genome-wide significance for risk of acquiring or severity of SAB [36,37]. A third larger GWAS study of 4701 SAB cases and 45,344 matched controls identified two SNPs that achieved genomewide significance for altered susceptibility to S. aureus infection in individuals of European ancestry (rs35079132: p = 3.8 × 10-8, and rs35079132 p = 3.8 × 10-8) [38]. These loci were located near the HLA-DRA and HLA-DRB1 genes in the HLA class II region. Using admixture mapping, that same genetic region of European origin was also identified in African Americans as associated with SAB at a genome-wide level of significance [39]. This discovery was the first of its kind in S. aureus research and built on the enlarging body of evidence linking HLA haplotypes to susceptibility and severity of bacterial infection [40–45].
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