Background: Over time the majority of the population experience some degree of exposure to Streptococcus pyogenes yet invasive infections are rare. Accordingly, we investigated host susceptibility across distinct clinical manifestations and ancestral populations.
Methods: We undertook a genome-wide association study of susceptibility in children and adults recruited in UK, Kenya and New Caledonia. Cases (n=161) were patients with microbiologically confirmed invasive infection including bacteraemia (n=75), empyema thoracis (n=37) necrotising fasciitis (n=34), other soft tissue infections (n=7) and septic arthritis (n=4). Controls (n=1,610) were healthy children and adults from the same populations, genotyped using the same array-based technology. Putative associations (p<10-5) were followed up in an independent study of children with acute febrile illness recruited in Europe (invasive S. pyogenes cases, n=122; healthy controls, n=1,220).
Results: In the discovery analysis, we identified 25 genomic regions putatively associated with susceptibility. Of these, a single locus on chromosome 1 replicated in the follow-up analysis, the lead variant conferring a 1.8-fold increased risk of invasive S. pyogenes across all populations combined (rs554742, OR=1.78, 95%CI 1.46-2.17, p=1.5x10-8) with limited heterogeneity (Q-test, p=0.63). Moreover, based on publicly available GTEx Project data, the minor allele, which has a frequency of 16% globally, is strongly associated with reduced expression of SLC35A3 in multiple relevant tissues including skin and lung.
Discussion: These results identify the UDP-N-acetylglucosamine transporter, SLC35A3, a nucleotide sugar transporter required for glycosylation of numerous proteins involved in immunity and the extracellular matrix, as a previously unrecognised component of host defence against invasive S. pyogenes infection.