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

Abstract

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.

A common allele of HLA mediates asymptomatic SARS-CoV-2 infection

“…A study from England has recently reported a suggestive association of HLA-DRB1*04:01 with asymptomatic infection. 27 While our results did not corroborate this association for HLA-DRB1*04:01 alone, we did find that this allele enhanced the effect of HLA-B*15:01 when the pair were in combination. We note that this is the HLA-DRB1 allele most commonly associated with HLA-B*15:01 in individuals in the U.S. who self-identify as White, and thus it is difficult to differentiate a real effect from one related to linkage disequilibrium between these loci.…”

“…24 To date, very few studies have directly examined HLA associations with infection, with mixed and inconclusive results in relatively small cohorts. [26][27][28] Larger studies that relied on genome-wide data to impute HLA failed to find robust associations with disease. 8,29 However, these studies focused primarily on hospitalized patients with severe disease course.…”

Does immune recognition of SARS-CoV2 epitopes vary between different ethnic groups?

“…Noticeably, HLA-DRB1*01:01 has been shown to be negatively associated with mortality rate of hospitalized patients ( Romero-López et al, 2021 ) and was found to be most abundant among European (EUR) super-population. Yet another study reported a significantly lower frequency of the haplotype DQA1*01:01‐DQB1*05:01‐DRB1*01:01 among the asymptomatic group when compared to patients with high severity ( Langton et al, 2021 ). In contrast to our observations, this would indicate at a diminished capability to identify and counter SARS-CoV2 invasion among individuals harboring HLA-DRB1*01:01.…”

“…The Human Leukocyte Antigens (HLA) system, a major determinant of our ability to detect and neutralize an invading pathogen, is encoded by the Major Histocompatibility Complex (MHC) genes located on chromosome-6. This system has been shown to play a crucial role in the manifestation and outcome of Covid-19 infection (Amoroso et al, 2021; Correale et al, 2020 ; Langton et al, 2021 ; Malkova et al, 2021 ; Pisanti et al, 2020 ; Shkurnikov et al, 2021 ). MHCs, which are further categorized into classes-I and II, are highly polymorphic and are known to vary significantly among individuals of different ethnicities.…”

The First Chemically-Synthesised, Highly Immunogenic Anti-SARS-CoV-2 Peptides in DNA Genotyped Aotus Monkeys for Human Use

“…This suggested that people carrying these specific HLA-DRb1* alleles would have a greater probability of developing 'protective' LiViNAbdependent immune responses when immunised with COLSARSPROT. This would have improved protection against this life-threatening disease since several studies have shown some fatality or severity to be associated with HLA-DRb1*1301 in South Asian people (78), with HLA-DRb1*0401 in Europeans (79) and HLA-DRb1*0901 in Japanese people (80), i.e. COLSARSPROT contains peptides inducing high LL-or SL-LiViNAbI.…”