HLA Genotype and its effect on the severity of COVID-19 Infections

Isabelle Ferenczi introduces the importance of Human Leukocyte Antigens and their potential role in determining a given patient’s response to COVID-19 infection.

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A brief introduction to HLA

Human Leukocyte (white blood cell) Antigens (HLA), are proteins that have a vital role in presenting foreign peptide (short amino acid chain) antigens in the bloodstream. Antigens are important when it comes to triggering an immune response. The HLA system is the most polymorphic, meaning a varied and adaptable, genetic system in humans. Different environments and selective pressures around the world are likely to be the reason behind such a vast HLA variety. This diversity may have resulted from HLA’s role in presenting infectious agents prevalent in different areas (Choo, 2007).  Furthermore, specific HLAs are associated with more than 100 different diseases including diabetes, asthma, and more. However, there is still a lot to learn about the HLA expression profile (the measurement of the activity of this gene) and associated varying diseases (Shiina, Hosomichi, Inoko, and Kulski, 2009). 

The HLA proteins are encoded by the classical HLA genes (Langton et al., 2021).  HLA genes provide the information necessary to manufacture specific proteins which in this case are glycoproteins that bind to small molecules on the exterior membrane of cells. These binding sites are peptides. There are two different classes of HLA molecules; Class 1 HLA molecules are found on all nucleated cells (those which contain a nucleus). These nucleated cells will then present these peptides to T-cells, which are “important for immune defense against intracellular pathogens”. Class 2 HLA molecules are only found on specialised cells of the immune system called antigen-presenting cells. These present the peptides to T-helper cells, another group of immune cells.

There are many slight differences in the genetic code for the HLA molecules carried by all of us. These small genetic differences result in proteins consisting of slightly different sequences of amino acids (the protein building blocks). The variations in genetic code give rise to closely related families of genes called alleles. In the case of HLAs, the different amino acid sequences influence the 3-dimensional structure of the peptide-binding groove (Langton et al., 2021). The peptide-binding groove refers to a cleft on HLA molecules. The size of this cleft determines which peptide fragments from the invading pathogens are presented and hence influence the T-cell response (Langton et al., 2021). It is known that HLA allele variation influences susceptibility or resistance to other infectious diseases including tuberculosis and malaria among others (Langton et al., 2021). Moreover, it is postulated that due to the highly evolved MHCs present in bats, this makes them a reservoir of coronaviruses (Langton et al., 2021). MHCs (Major Histocompatibility complexes) is a term used interchangeably with HLA in humans, as these refer to a group of genes that code for proteins that help the immune system recognise foreign elements. Therefore, the variation in the genetic code for HLA can affect the peptide-binding groove and as such can influence the T-cell’s ability to respond to invading pathogens.

It is known that HLA allele variation influences susceptibility or resistance to other infectious diseases including tuberculosis and malaria among others.

The HLA and Covid-19 Study

The severity of COVID-19 infection varies at both the individual and populational levels. At the individual level, trends have shown that older male patients with pre-existing conditions and a high BMI (Body Mass Index) are at an increased risk of an adverse reaction to infection (Langton et al., 2021).  Langton et al conducted a study exploring whether these discrepancies in the severity of infection were correlated to differences in HLA genes. Next-generation sequencing (used to determine sequences of DNA) was used to analyse both class 1 and class 2 classical HLA genes of 147 individuals of European descent experiencing variable clinical outcomes following COVID-19 infection. Results were compared to 69 asymptomatic hospital workers. 

Software can be used to virtually construct peptide-binding grooves encoded by an individual’s HLA genotype and used to calculate the binding affinity between the specific binding groove and naturally occurring peptides. It was found that HLA alleles interact with age, sex, and BMI to determine clinical outcomes upon COVID-19 infection. The paper found a significant difference in a particular HLA allele frequency in severely affected patients compared to the asymptomatic staff. It was found that 30% of Europeans carry this said allele however there are 50 subtypes of this allele. Data analysis suggested that this allele is ‘protective’. Conversely, other alleles are thought to be “associated with an increase in disease severity”. 

The alleles that were observed at a lower frequency in the asymptomatic group compared to the background population, suggested that these alleles are associated with an increased likelihood of developing symptoms or that the response to COVID-19 isn’t primarily dependent on the secondary immune response. 

Previous work found that there was a correlation between COVID-19 mortality and latitude (distance from the equator), countries at higher latitudes have populations with a higher risk of COVID-19 mortality. On the other hand, there is an inverse relationship between mortality and longitude (the distance around the globe) (Sanchez-Mazas, Buhler, and Nunes, 2013). Latitude and longitude also correlate to HLA genotype frequencies. Therefore there is likely a relationship between HLA genotype frequencies and COVID-19 mortality. The alleles most strongly related to a severe reaction to COVID-19 are seen at a higher frequency farther away from the equator, such as northwest European populations which have the highest predominance of these alleles.

ConclusionLangton et al have shown that HLA alleles interact with varying factors to influence the susceptibility of developing severe clinical outcomes to COVID-19. This is important as throughout the pandemic it has been noted that the virus has disproportionately affected certain ethnic groups in comparison to others, specifically Black, Asian and Minority Ethnic people (BAME). Not only do BAME groups in the United Kingdom have a higher risk of contracting the virus but also are more likely to have a more adverse reaction to infection. It was found in a UK government-requested inquiry by the Office for National Statistics (ONS) that black males are 3.3 times more likely to experience fatal clinical symptoms from COVID-19 than their white counterparts, and black females are 2.4 times more at risk than those of white ethnicity. Bangladeshi, Pakistani and Indian backgrounds in the UK are also at a higher risk than those from a white background (Office for National Statistics, 2020). Note, however, that these statistics are specific to BAME groups in the United Kingdom. Unlike the study commissioned by the ONS, Langton’s study is limited to individuals of European descent. While this study is important in establishing our initial understanding of the impact of HLA genotypes on COVID-19 mortality, it is vital that future studies continue this research with patients of varying ethnicities.

Written by Isabelle Ferenczi and edited by Diana Jorge.

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