Invasive group A streptococcal (GAS) disease is uncommon but carries a high casefatality rate relative to other infectious diseases. Given the ubiquity of mild GAS
infections, it remains unclear why healthy individuals will occasionally develop lifethreatening infections, raising the possibility of host genetic predisposition. Here, we
present the results of a case-control study including 43 invasive GAS cases and
1,540 controls. Using HLA imputation and linear mixed-models, we find each copy of
the HLA-DQA1*01:03 allele associates with a two-fold increased risk of disease
(odds ratio 2.3, 95% confidence interval 1.3-4.4, P=0.009), an association which
persists with classical HLA typing of a subset of cases and analysis with an
alternative large control dataset with validated HLA data. Moreover, we propose the
association is driven by the allele itself rather than the background haplotype. Overall
this finding provides impetus for further investigation of the immunogenetic basis of
this devastating bacterial disease.