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

David J Langton,John Burn,Shonali Natu,Stephen C Bourke,Gabrielle Reiff,Carlos Echevarria,Benedicte A Lie,Rebecca Darlay

doi:10.1111/tan.14284

Abstract

The impact of COVID‐19 varies markedly, not only between individual patients but also between different populations. We hypothesised that differences in 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.

Highlights

Since it emerged in Wuhan, China in late 2019, COVID-19 has led to an unprecedented international crisis.[1]
We investigated whether previously well patients who required admission for treatment of COVID-19 infection have different HLA alleles compared to asymptomatic controls and the background population
As part of an ethically approved research study (‘Do major histocompatibility complex (MHC) genes play a role in the severity of COVID-19?’ IRAS project 283409; REC reference: 20/YH/0184) sponsored by North Tees and Hartlepool NHS FT, we compared the classical HLA gene frequencies in two groups: patients admitted with severe COVID infection and hospital staff who remained asymptomatic following exposure to COVID

Summary

| BACKGROUND

Since it emerged in Wuhan, China in late 2019, COVID-19 has led to an unprecedented international crisis.[1]. Through the process of evolution, viruses have exerted selective pressure on humans, meaning that some human populations exhibit marked genetically determined variations in their resistance or susceptibility to different endemic infectious organisms.[6] It is possible that reported regional variations in the impact of COVID may reflect these variations.[7,8,9]. In this respect, some of the most well described immune features belong to the major histocompatibility complex (MHC). We investigated whether previously well patients who required admission for treatment of COVID-19 infection have different HLA alleles compared to asymptomatic controls and the background population

| Study participants and recruitment

| Results

Findings

| DISCUSSION