The influence of HLA genotype on the severity of COVID-19 infection

HLA. 2021 Jul;98(1):14-22. doi: 10.1111/tan.14284. Epub 2021 May 4.


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. Using next generation sequencing, we analysed the class I and class II classical HLA genes of 147 individuals of European descent experiencing variable clinical outcomes following COVID-19 infection. Forty-nine of these patients were admitted to hospital with severe respiratory disease. 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. Allele 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. We found a significant difference in the allele frequency of HLA-DRB1*04:01 in the severe patient compared to the asymptomatic staff group (5.1% vs. 16.7%, P = .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 = .007). Ordinal logistic regression modelling confirmed the significant influence of DRB1*04:01 on the clinical severity of COVID-19 observed in the cohorts. These alleles are found in greater frequencies in the North Western European population. This regional study provides evidence that HLA genotype influences clinical outcome in COVID-19 infection. Validation studies must take account of the complex genetic architecture of the immune system across different geographies and ethnicities.

Keywords: COVID; COVID-19; HLA; genetics; latitude; virus.

MeSH terms

  • Alleles
  • COVID-19*
  • Gene Frequency
  • Genotype
  • HLA-DQ Antigens / genetics
  • HLA-DQ alpha-Chains
  • HLA-DQ beta-Chains / genetics
  • HLA-DRB1 Chains / genetics
  • Haplotypes
  • Humans
  • SARS-CoV-2


  • HLA-DQ Antigens
  • HLA-DQ alpha-Chains
  • HLA-DQ beta-Chains
  • HLA-DRB1 Chains