THE INFLUENCE OF HLA GENOTYPE ON SUSCEPTIBILITY TO, AND SEVERITY OF, COVID-19 INFECTION

Langton, D. J.; Bourke, S. C.; Lie, B. A.; Reiff, G.; Natu, S.; Darlay, R.; Burn, J.; Echevarria, C.

Background The impact of COVID-19 varies markedly, not only between individual patients but also between different populations. We hypothesised that differences in human leukocyte antigen (HLA) genes might influence this variation. Methods Using next generation sequencing, we analysed the class I and class II classical HLA genes of 147 white British patients with variable clinical outcomes. 49 of these patients were admitted to hospital with severe COVID infection. They had no significant pre-existing comorbidities. We compared the results to those obtained from a group of 69 asymptomatic hospital workers who evidence of COVID exposure based on blood antibody testing. Allelic frequencies in both the severe and asymptomatic groups were compared to local and national healthy controls with adjustments made for age and sex. With the inclusion of hospital staff who had reported localised symptoms only (limited to loss of smell/taste, n=13) or systemic symptoms not requiring hospital treatment (n=16), we carried out ordinal logistic regression modelling to determine the relative influence of age, BMI, sex and the presence of specific HLA genes on symptomatology. Findings We found a significant difference in the allelic frequency of HLA-DRB1*04:01 in the severe patient compared to the asymptomatic staff group (5.1% versus 16.7%, p=0.003 after adjustment for age and sex). There was a significantly lower frequency of the haplotype DQA1*01:01/DQB1*05:01/DRB1*01:01 in the asymptomatic group compared to the background population (p=0.007). Ordinal logistic regression modelling confirmed the significant influence of DRB1*04:01 on the clinical severity of COVID-19 observed in the cohorts. Interpretation This study provides evidence that patient age, sex, BMI and HLA genotype interact to determine the clinical outcome of COVID-19 infection.