Some experts say that reports linking certain blood types to lower infection risks are ‘flawed’

Recently, the New England Journal of Medicine published a study that found links between Covid-19 and certain genetic and blood-type variables. While the authors emphasized the potential usefulness of their gene-related findings, which implicated clusters of genes on a specific chromosome in severe Covid-19 cases, most of the media attention centered on the blood-type findings. Among the more than 1,500 Italian and Spanish patients with the coronavirus included in the study, infection appeared to be less common among people with blood type O and more common among people with blood type A. (The type B’s fell somewhere in between.)

The study’s blood-type findings closely mirrored the results of an earlier paper from China, which also found an elevated infection risk among type A’s and lower risk among type O’s. “There are now several studies confirming the association, which is also seen for [SARS],” says Tom Karlsen, MD, PhD, co-author of the new study, and a professor of internal medicine at the University of Oslo in Norway.

SARS and Covid-19 stem from genetically related coronaviruses. So it makes some sense that if a certain blood type is associated with a lower risk for one of these infections, it could also lower a person’s risk for the other. There are also several well-established connections between blood type and infectious diseases; for example, type O blood is protective against malaria but is associated with more severe cases of cholera.

The new Covid-19 findings surely produced some relief in people who are type O and dread in those who are type A. But some experts who have looked at the research say that the findings are questionable — and may ultimately prove to be either inaccurate or misleading.

“I keep getting emails from people asking me if they should get blood typed, and I tell them definitely not!” says Laura Cooling, MD, a professor and associate director of transfusion medicine at the University of Michigan.

Cooling says that some American researchers, herself included, have been looking at blood-group data since the early days of the outbreak. They have not seen meaningful correlations. “I don’t think it’s going to pan out,” she says of the new paper’s findings. “I think that the contribution of blood group to an individual’s risk is going to be minor compared to underlying heart disease or obesity or hypertension, or those other risk factors that have been identified.”

She’s not alone. “I think the apparent associations are not correct and are based on a methodology flaw,” says Walter Dzik, MD, a pathologist at Massachusetts General Hospital who has examined the relationship between ABO blood types and Covid-19 and has not found a link.

To understand their skepticism, it helps to know how blood groups and infectious pathogens interact — for better or worse.

The connection between blood type and infection risk

The surface of every red blood cell is coated with various protein and sugar molecules. These molecules shore up the walls of blood cells, assist in chemical reactions, and perform other jobs. There are hundreds of these blood-cell molecules, which vary from one person to the next and are sometimes termed “antigens” because they elicit a response from the body’s immune system.

Experts lump some of these molecules together into “blood groups.” One example is the ABO blood group, which refers to certain sugars that decorate red blood cells. Different versions of a single gene lead to the presence or absence of sugars, which determine if someone is blood type A, type B, or type AB. In the case of type-O folks, that single gene is mutated and nonfunctional.

What do blood groups have to do with the novel coronavirus or other infectious diseases? The antigens and immune antibodies associated with each blood group may explain some associations, says James Fleckenstein, MD, a professor of medicine and molecular microbiology at the Washington University School of Medicine in St. Louis. “It’s possible that people with different blood groups mount different immune responses to pathogens such as SARS-CoV-2,” he says.

Alternatively, he says that blood groups can be “receptors” for pathogens or the proteins they produce. “Many pathogens rely on glycans — sugars — to attach to their host targets,” he explains. “Because molecules present on red blood cells are also expressed on mucosal surfaces that the virus might encounter” — such as the walls of the lungs or intestines — “they could be involved in the viral binding or uptake required for viral proliferation.”

“I think that the contribution of blood group to an individual’s risk is going to be minor compared to underlying heart disease or obesity or hypertension, or those other risk factors that have been identified.”

There are still other potential explanations. Some research has linked Covid-19 to abnormal blood clotting, and some blood-group antigens can influence how blood coagulates.

Why do human beings possess these blood-based differences? One theory is that this variability helps ensure that not everyone will succumb to whatever form of plague or pestilence is making the rounds. In areas where certain forms of infection are present, and have been for a long time, some infection-fighting blood groups are more common. “In the Ganges River Delta there’s a lower incidence of type O, and people have widely suspected that’s from selective pressure from cholera,” Fleckenstein says. “You see these kinds of patterns around the globe.” It may be that, in these areas, people with certain blood types were more likely to survive and pass their genes onto later generations.

But while there’s ample reason for doctors and researchers to go looking for connections between blood groups and SARS-CoV-2, Harvard’s Dzik says that the findings to date linking type-O individuals to lower rates of Covid-19 are likely inaccurate.

He points out that Covid-19 has hit people of African and Latino ancestry especially hard, but that blood type O — the ostensibly protective type — is more common among these groups than among Caucasians. (By some estimates, 57% and 50% of Hispanics and Blacks are type O, respectively, while that’s true of just 45% of Caucasians.) “So, right from the beginning, the reported association was the opposite of what one might expect to find if any association of ABO and Covid-19 existed,” he says.

‘Flawed’ findings?

Regarding the new NEJM study, Dzik says that he sees a potential methodology problem. “It has to do with the comparison group,” he says, referring to the nonpatient group against which the Covid-19 patient data was assessed.

“You may still get severe Covid-19 with blood type O. For now, the insight [of this data] is relevant to future research, not clinics.”

The majority of this control group was composed of blood donors. “It is widely known that the ABO distribution among blood donors is not representative of the general population,” he says. “Group-O blood donors are preferred always, everywhere, because their red blood cells can be used for any recipient.” If group-O folks were overrepresented in the control group, this would make group O’s appear to be underrepresented in the patient group, which is what the study found, he says.

University of Michigan’s Cooling points out another possible issue with the study team’s methodology. “They were inferring blood types based on three genetic [single nucleotide polymorphisms] — they never physically typed the patients’ red blood cells,” she says. By this, she means blood types were assessed based on small pieces of DNA information that correlate — though not perfectly — with blood type. Because of this, she says that the study team “may have overcounted A’s and B’s and undercounted O’s.”

The NEJM study authors themselves highlighted some of these same drawbacks in their paper. “We were very aware of these potential issues and made the greatest efforts possible to query for what such sources of bias would potentially mean,” says University of Oslo’s Karlsen, regarding the problem of relying on blood types collected from donor pools. He adds: “The ABO finding is puzzling, we agree, and caused quite an amount of reflections and extra efforts in our group.” He said he and his co-authors welcome independent scrutiny and follow-up work on their findings.

Even if the blood-type research pans out, it wouldn’t mean much for the average person. These studies have found that type O’s are at reduced risk for infection — but not that their risk is zero. (The Chinese study, for example, found that type O’s comprised about 26% of Covid-19 patients, while type A’s made up about 34%.) “You may still get severe Covid-19 with blood type O,” Karlsen says. “For now, the insight [of this data] is relevant to future research, not clinics.”

Cooling says that other aspects of the new study — such as data related to Covid-involved gene clusters — may very well prove helpful down the road. But for now, people shouldn’t get wrapped up in the blood-type hype. “[Having blood type O] is not putting an ‘S’ on your chest and becoming Superman,” she says. “If there is any protection there, it’s going to be weak.”

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