Do Your Genes Predispose You to COVID-19?

Since the start of the COVID-19 pandemic several months ago, scientists have been puzzling over the different ways the disease manifests itself. They range from cases with no symptoms at all to severe ones that involve acute respiratory distress syndrome, which can be fatal. What accounts for this variability? Might the answer lie in our genes?

Coronaviruses have raised such questions for more than 15 years. In researching the 2003 outbreak of severe acute respiratory syndrome (SARS), Ralph Baric and his colleagues at the University of North Carolina at Chapel Hill identified a gene that, when silenced by a mutation, makes mice highly susceptible to SARS-CoV, the coronavirus that causes the disease. Called TICAM2, the gene codes for a protein that helps activate a family of receptors, called toll-like receptors (TLRs), that are involved in innate immunity, the first line of defense against pathogens.

Attention has now shifted to SARS-CoV-2, the new coronavirus that causes COVID-19. And TLRs have once again drawn researchers’ interest—this time to help explain the excess number of men who suffer from severe infections.

Men made up 73 percent of severe cases of COVID-19 in intensive care in France, according to a national survey published April 23. Behavioral and hormonal differences may be partially responsible. But genes may also factor into the mix. Unlike men, women have two X chromosomes and so carry double the copies of the gene TLR7, a key detector of viral activity that helps boost immunity.

The genetics of blood groups may offer some insight into whether you are liable to be infected with the virus. In late March Peng George Wang of the Southern University of Science and Technology in China and his colleagues released the results of a preprint study—not yet peer-reviewed—that compared the distribution of blood types among 2,173 COVID-19 patients in three hospitals in the Chinese cities of Wuhan and Shenzhen with that of uninfected people in the same areas. Blood type A appears to be associated with a higher risk of contracting the virus, whereas type O offers the most protection for reasons that have yet to be determined.

The earlier SARS outbreak also offers lessons. Blood types bear two different kinds of saccharide (sugar) molecules on the surface of red blood cells. One corresponds to type A, the other type B. Each kind of molecule is produced by an enzyme whose gene exists in two forms (one for type A and the other for type B). A third gene variant encodes an inactive enzyme: type O (from the German ohne, meaning “without”). A person possessing variants A and B of the enzyme has type AB blood.

Each sugar, A or B, may act as an antigen. It can trigger the production of antibodies that target the antigens it lacks, which is why care must be taken with blood transfusions. In the ABO blood group system, type O blood is the richest in antibodies—possessing both anti-A and anti-B—whereas type AB blood does not have either of them.

In 2008 Jacques Le Pendu of the University of Nantes in France and his colleagues investigated an in vitro model of SARS-CoV. The researchers showed that the binding of the virus’s protein S to a cell’s ACE2 (angiotensin-converting enzyme 2) receptor, which is necessary for infection to take place, is inhibited by the anti-A antibody, though data on the anti-B antibody are still lacking.

A close relative of ACE2 in blood pressure control is angiotensin-converting enzyme 1 (ACE1). The ACE1 D gene, one of several genetic variants of the enzyme, is associated with low levels of expression of the ACE2 gene. As a result, cells contain fewer of the receptors that allow infection by SARS-CoV. The frequency of ACE1 D differs from one country to another, particularly in Europe, which raises the question of whether the geographical distribution of this variant correlates with COVID-19 prevalence. Might it reflect the epidemiology of the disease on a global scale? Marc De Buyzere and his colleagues at Ghent University in Belgium found that to be the case.

Using data from 25 countries (spanning a region from Portugal to Estonia and from Turkey to Finland), the researchers showed that 38 percent of the variability in disease prevalence is explained by the frequency of the ACE1 D gene. A similar correlation turned up for mortality statistics. The researchers also noted that the ACE1 D gene is less frequent in two Asian countries severely hit by SARS-CoV-2.

A further genetic component of susceptibility to the new coronavirus may lie in the genes that encode human leukocyte antigens (HLAs), a set of proteins that keep the human immune system from attacking the body itself. These proteins make up the major histocompatibility complex (MHC), which marks “self” and distinguishes it from “nonself.” Reid Thompson and his colleagues at the Oregon Health & Science University discovered a link between specific HLA genes and the severity of COVID-19.

Carriers of a variant called HLA-B*46:01 appear to be particularly susceptible to SARS-CoV-2, as was previously shown to be the case with SARS-CoV. In contrast, the HLA-B*15:03 variant may provide some protection. According to the researchers, identification of a person’s HLA genes, which can be done quickly and inexpensively, may help to better predict the severity of disease—and even to identify those who would benefit most from vaccination.

Several projects are underway to investigate the genetic variants that influence SARS-CoV-2 infection in greater depth. Andrea Ganna of the University of Helsinki has launched the COVID-19 Host Genetics Initiative, which aims to mobilize the international community of geneticists working on this topic. Jean-Laurent Casanova of the Necker Hospital for Sick Children in Paris and the Rockefeller University is coordinating a similar effort to identify genetic variants that promote the development of particularly severe forms of COVID-19 in people under 50 years of age.

We may not all be equal when it comes to SARS-CoV-2. But identifying why these inequalities exist could help reduce them.