With all of the hype surrounding the COVID-19 pandemic, it’s easy to get lost in the numbers of mortality rates and the quantity of people infected. Understanding which individuals in the world are most at risk goes far beyond looking at factors like age and gender. In fact, few have questioned: how does inter-individual genetic variability affect the probability of a person contracting a disease, such as COVID-19, and how does this genetic variability correlate with the severity of a disease? This paper does not provide any concrete solutions to the current COVID-19 pandemic. Instead, it serves as a high-level introduction to the importance of analyzing the specific genetic makeup of individuals in order to determine which people are most susceptible to what diseases, such as COVID-19. My ultimate objective is for this paper to serve as a catalyst to greater public interest and discussion surrounding immunoprofiling in order to protect the most susceptible populations. I am not a scientist, I am simply one of the many curious people out there who is attempting to learn more about this situation. With that said, let’s begin.
The concept of linking genetic predisposition of individuals to illness, such as SARS (which is of most relevance to this particular pandemic), is nothing new. However, before I go into any examples from scientific literature, you must first acquaint yourself with a few key scientific terms: the Human Leukocyte Antigen (HLA) system, Major Histocompatibility Complex (MHC) system, and allele.
The MHC is the group of genes that code for proteins found on the surfaces of cells that help the immune system recognize foreign substances. In humans, the MHC is also called the HLA. According to a paper entitled “Association of HLA class I with severe acute respiratory syndrome coronavirus infection,” the HLA system is “Widely used as a strategy in the search for the etiology of infectious diseases and autoimmune disorders.” In other words, it is common to use the HLA system as a method to identify which individuals are susceptible to what maladies, such as SARS (Severe Acute Respiratory Syndrome).
To make things even more clear, let’s break down that HLA jargon even further. Recall that the HLA are proteins found on the surface of cells that help the immune system identify the “bad guys” that are trying to harm your immune system. The HLA system has three groups of class I genes: HLA-A, HLA-B, and HLA-C (there are also class II and class III genes). Each group of these HLA genes comes in a bunch of different varieties, which are known as alleles, and each allele is assigned a specific number to identify it (for example, HLA-B*46). Moreover, alleles that are similar in nature are further grouped into subtypes with very specific identifications (for example, HLA-B*4601). Now Let’s put this information into action with a real world example.
The scientific research paper mentioned above (which was published in 2003 during the time of the SARS epidemic) discovered that in Taiwan, “When analyzing infected SARS patients and high risk health care workers groups, HLA-B*4601 (OR = 2.08, P = 0.04, Pc = n.s.) and HLA-B*5401 (OR = 5.44, P = 0.02, Pc = n.s.) appeared as the most probable elements that may be favoring SARS coronavirus infection.” Essentially, the study found that Taiwanese individuals with the specific HLA-B*4601 and HLA-B*5401 alleles may be at risk for contracting SARS. Moreover, data confirms that HLA-B*4601 is highly prevalent in eastern Asia, with some 400 million individuals carrying this specific HLA variant. Also, while this HLA variant is most frequent in eastern Asia, other populations may also carry this variant, and not all eastern Asians carry HLA-B*4601 either (remember, every single person is different!).
Furthermore, the reason why some populations may have greater frequencies of certain HLA variants than other populations (such as Taiwanese individuals and the HLA-B*4601 allele) is due to host-environment and gene-environment interactions. For example, a paper called “The Adaptive Change of HLA-DRB1 Allele Frequencies Caused by Natural Selection in a Mongolian Population That Migrated to the South of China,” explains this concept in more detail:
Pathogen-driven balancing selection determines the richness of human leukocyte antigen (HLA) alleles. Changes in the pathogen spectrum may cause corresponding changes in HLA loci. Approximately 700 years ago, a Mongolian population moved from the north of China to the Yunnan region in the south of China. The pathogen spectrum in the south of China differs from that in the north. In this study, changes in the HLA genes in the Yunnan Mongolian population, as well as the underlying mechanism, were investigated… analysis showed that the HLA-DRB1 genes in both Mongolian populations were under balancing selection. However, the sites under natural selection changed. We proposed that the dramatic change of HLA frequencies in southern Mongolian was caused by a combination of inter-population gene flow and natural selection. Certain diseases specific to the south of China, such as malaria, may be the driving force behind the enhanced DRB1*12:02:01 frequency.
To supplant the information above, an excerpt from the Chapter 4 of the 2009 book Chesley's Hypertensive Disorders in Pregnancy (Third Edition) called “Genetic Factors in the Etiology of Preeclampsia/Eclampsia,” by Kenneth Ward, Marshall D. Lindheimer states that:
Gene–environment interactions are situations in which environmental factors affect different individuals differently, depending upon genotype, and in which genetic factors have a differential effect, depending upon attributes of the environment. The possible number of gene–environment interactions involved in a complex disease should daunt researchers more than the genomics of that disease.
Before I bring the discussion back to HLA variants and their potential role in pinpointing susceptible populations, it is necessary for me to give you a brief rundown of some immune system terms: B and T cells, lymphocyte, antigen, epitope, and antibody. B and T cells are short for B and T lymphocytes, and lymphocytes are a type of white blood cell that helps us combat infections. As the graphic below demonstrates, B cells help to attack invaders outside of cells, and T cells help to attack invaders inside the cells. Together, B and T cells help to defend your immune system against illness. Antigens are “molecules capable of stimulating an immune response. Each antigen has distinct surface features, or epitopes, resulting in specific responses." A B-cell epitope is the antigen portion binding to the antibody, and T-cell epitopes are “presented on the surface of an antigen-presenting cell, where they are bound to MHC molecules.”
Now that you have been briefed on a moderate amount of information on the immune system, I will introduce to you a paper that was published on the 25th of February, 2020, called “Preliminary Identification of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies.” On a very high-level, the researchers utilized existing data on SARS-COV (responsible for the 2003 SARS outbreak) and its genetic similarity to COVID-19 in order to accelerate progress towards a vaccine. More concretely, the researches screened “experimentally-determined SARS-CoV-derived B cell and T cell epitopes in the immunogenic structural proteins of SARS-CoV,” identified a set of these epitopes from “the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins,” and performed a “population coverage analysis of the associated MHC alleles” on these T cell epitopes in order to propose, “a set of epitopes that is estimated to provide broad coverage globally, as well as in China.”
As you can see, utilizing HLA variants as a tool to help determine which populations are most susceptible is a widely used technique. A paper titled “Association Between HLA Gene Polymorphism and the Genetic Susceptibility of SARS Infection” substantiates this further:
Numerous studies have demonstrated that many severe diseases, such as cancer, atherosclerosis, coronary heart disease, diabetes, schizophrenia, and high blood pressure, have significant genetic predispositions. In addition, some infectious diseases caused by bacteria and viruses have significant individual genetic predispositions. The human immune and genetic system most closely related to genetic predisposition to disease is the major histocompatibility complex (MHC).
… The rapid development of advanced technologies in modern molecular biology and their wide applications to HLA studies have effectively promoted studies of HLA mechanisms and their associations with disease, leading to significantly increased accuracy of disease association analysis.
So, what is the bottom line to all of this? Why did I even choose to write about all of this in the first place? In order to address COVID-19, we need to use all of our resources in addition to looking at the genetics of the virus. It is worth exploring immunoprofiling as a tool to combat diseases, especially given our current data mining, data analytics, and machine learning capabilities. Because of this pandemic, we now have a rich mass of data that can help tell us which individuals are most susceptible. We need to give scientists more access to this data so that the full power of immunoprofiling can be unleashed, and so that we can finally usher in the new age of personalized medicine that the healthcare system has been promising us for years.