Why Blood Type Seems to Be Linked With COVID-19 Risk

Since the early months of the COVID-19 pandemic, scientists have investigated whether ABO blood group is related to the risk of SARS-CoV-2 infection and illness.

After all, nearly 20 years ago, researchers reported that type O blood was associated with a lower risk of the original SARS. In addition, other studies had linked type O blood to a higher risk of infection by cholera, norovirus, and Helicobacter pylori.

“It’s probably why we still have ABO blood groups in the population,” with each of them having an advantage, depending on the disease, Sean Stowell, MD, a transfusion specialist at the Brigham and Women’s Hospital and Harvard University in Boston, explained in an interview.

Perhaps not surprisingly, given the earlier SARS observations, Stowell said that most studies of the relationship between SARS-CoV-2 and blood group have found that, all other things being equal, people with type A were more likely to become infected than people with type O. Although some studies have found no relationship between blood type and COVID-19 risk, none has linked type O to a higher risk of SARS-CoV-2 infection.

Why would blood group make any difference to SARS-CoV-2? Several new studies offer possible explanations. One from Stowell and colleagues, recently published in Blood, suggests that having type A blood makes SARS-CoV-2 “stickier” to host cells.

Early in the pandemic, when Stowell was on the faculty at Emory University, the US Centers for Disease Control and Prevention asked him and his colleagues to develop a serology test to check for evidence of SARS-CoV-2 infection.

Their test, which the Food and Drug Administration authorized for emergency use, used a recombinant form of the receptor-binding domain (RBD) region of the SARS-CoV-2 spike protein to detect antibodies in blood specimens. Targeting the RBD seemed to make the most sense “because it was the thing that sticks to cells,” Stowell explained, “which is why we started looking at it more carefully.”

That’s when Stowell’s team noticed something surprising: SARS-CoV-2’s RBD resembled an ancient family of carbohydrate-binding proteins called galectins, present in every animal species. Analysis by Stowell and his collaborators revealed that some galectins shared up to 11% of their nucleotide sequence with the SARS-CoV-2 RBD.

“We were not expecting that at all,” he said.

Some galectins have been shown to engage ABO antigens, which are carbohydrates—sugars, to be precise. Perhaps those antigens were the reason why the SARS-CoV-2 RBD seemed to find blood type A sweeter than blood type O, Stowell and his colleagues speculated.

SARS-CoV-2 enters cells through the angiotensin-converting enzyme 2 (ACE2) receptors on their surface. The receptors’ levels vary even among individuals with the same blood type.

So Stowell’s team undertook the painstaking task of engineering Chinese hamster ovary (CHO) cells that expressed both ACE2 and either the blood group A antigen or the blood group O antigen found on epithelial cells, which line the respiratory tract from the nose to the lungs. These antigens differ slightly from those found on red blood cells.

“The virus isn’t trying to infect our blood cells. The virus is trying to infect our lungs,” Stowell explained.

It took a year and a half to engineer the CHO cells. Once the cells were ready, the researchers investigated whether the type of blood group antigen they expressed influenced how well SARS-CoV-2 bound with them. They also compared the binding specificity of the SARS-CoV-2 RBD with that of galectins, specifically the C-terminal of Gal-4 (Gal-4C), which, they’d found, interacted with blood group antigens, and used Gal-1, which did not interact with the antigens, as a control.

• Although the CHO cells had identical levels of ACE2 receptors, those that expressed the blood group A antigen were significantly more likely to be infected with SARS-CoV-2 than those that expressed the blood group O antigen.

• Incubating the CHO cells with Gal-4C inhibited SARS-CoV-2 infection of cells that expressed blood group A but not blood group O. Because of its similarity to the RBD, Gal-4C had blocked SARS-CoV-2 from binding with cells expressing the A antigen, reducing the ability of those cells to facilitate RBD interactions with their ACE2 receptors.

• Incubating Gal-1 with the CHO cells made no difference in SARS-CoV-2 infection of either the A-expressing cells or the O-expressing cells. This was as expected because that particular galectin doesn’t play favorites when it comes to blood group antigens.

• Both the Delta and Omicron variants of the virus preferred the blood group A–expressing cells, but Omicron’s proclivity for the A antigen was even stronger.

• Although the researchers did not engineer CHO cells that expressed blood group B antigen, an additional analysis found enhanced Delta and Omicron RBD affinity for blood type B compared with blood type O.

“The virus still requires ACE2 to get in [cells],” Stowell pointed out. “The blood group A antigen on the cells just makes the virus a little stickier to the cells.” In other words, he said, having blood group A helps SARS-CoV-2 stick around and locate the ACE2 receptors on cells.

The findings also suggest that galectin-4 might modulate the influence of blood type on SARS-CoV-2 infection, although “galectin expression at sites of infection remains incompletely understood,” the researchers noted in their article.

“Thus,” they wrote, “variations in ACE2 levels, blood group A expression, and many other factors likely influence the overall risk of SARS-CoV-2 infection in a given population.”

Other new studies also add to the body of evidence around blood group and SARS-CoV-2 susceptibility and offer different potential mechanisms.

• Researchers in China enrolled patients hospitalized with COVID-19—137 with milder disease and 97 who were critically ill. They found that blood type wasn’t related to clinical outcomes, such as acute respiratory distress syndrome or death, but was associated with the likelihood of becoming infected with SARS-CoV-2. Further study showed that among healthy people, those with type A blood had significantly higher ACE2 protein levels than those with other blood types. That could help explain why type A blood was overrepresented among the patients hospitalized with COVID-19. In a laboratory experiment, the researchers found that the rate of SARS-CoV-2 RBD binding to red blood cells was highest among people with type A and lowest in people with type O blood.

• A study conducted by Danish researchers recruited 108 staff members at 3 hospitals who did not use personal protective equipment while caring for patients with undiagnosed COVID-19 from April to September 2020. Of the 108 staff unknowingly exposed to SARS-CoV-2, 34 became infected. Blood group O was associated with a lower risk of COVID-19 than blood groups A, B, and AB. High titers of preexisting natural anti-A antibodies, found in people with type O and type B blood, and anti-B antibodies, found in people with type O and type A blood, also were associated with a lower risk of COVID-19.

• Researchers in Italy assessed SARS-CoV-2 seroprevalence among 35 709 blood donors. Overall, 6.8% of them were found to be positive for SARS-CoV-2 immunoglobulin G antibodies. But the seroprevalence in donors with type A and type AB blood was 7.5% compared with 6.2% in donors with type O blood. Seroprevalence in donors with type B blood fell in the middle at 6.5%. The authors offered 2 hypotheses to explain their findings: the A antigen present in people with blood type A and AB plays a role in SARS-Cov-2 binding with ACE2 receptors. In addition, anti-A and anti-B antibodies, both of which are produced naturally in people with type O blood, might block the virus from sticking to cells, lowering the risk of infection.

“In my opinion, this paper provides direct evidence that blood group A antigen is a risk factor for SARS-CoV-2,” Xingbin Hu, MD, PhD, a transfusion medicine specialist at Xijing Hospital in Xi’an, Shaanxi, China, said about the study in Blood. “Undoubtedly, the mechanism between blood group antigens and SARS-CoV-2 infection susceptibility still needs further lab and clinical evidence,” Hu, a coauthor of the study of patients hospitalized in China, wrote in an email.

Hu’s team noted that their research shows that blood type A may be a biological marker for susceptibility to SARS-CoV-2 infection and might “provide new ideas for clinical diagnosis, treatment, and prevention of COVID-19.”

Of course, blood type isn’t a modifiable risk factor. Except in rare cases, mainly after receiving stem cells from a donor with a different blood type or developing certain malignancies or infections, blood type remains the same from birth to death.

“I don’t want people to worry,” said Stowell, who himself happens to have type A blood.

Although individuals who don’t have type O blood might be more likely to contract COVID-19, people with blood group O aren’t immune to the disease, Stowell emphasized.

That’s why everyone, no matter their blood type, should take steps to minimize their chances of SARS-CoV-2 infection, he noted, such as being up to date with vaccinations.

Published Online: August 16, 2023. doi:10.1001/jama.2023.15996

Conflict of Interest Disclosures: Dr Stowell reported consulting for Novartis, Cellics, Argenx, and Alexion and receiving speaking honoraria from Grifols. No other disclosures were reported.