By Markham Heid
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, but most of the media attention centred 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 Bs 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 As and lower risk among type Os.
“There are now several studies confirming the association, which is also seen for SARS (Severe acute respiratory syndrome),” 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 Covid-19 outbreak – and they have not seen meaningful correlations.
“I don’t think it’s going to pan out,” she says of the new paper’s findings, adding: “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.”
Cooling is 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 A-B-O 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.
Link 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 A-B-O 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-Os, 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, the professor says, 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.
Fleckenstein elaborates: “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.”
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 these blood-based differences?
One theory relating to why human beings possess these blood-based differences 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 say, adding: “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 is 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.
Dzik 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 per cent and 50 per cent of Hispanics and Blacks are type O, respectively, while that’s true of just 45 per cent 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,” Dzik says.
Are the findings flawed?
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 non-patient group against which the Covid-19 patient data was assessed.
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,” Dzik says.
He adds: “Group O blood donors are preferred always, everywhere, because their red blood cells can be used for any recipient.” If group Os were overrepresented in the control group, this would make them appear to be underrepresented in the patient group, which is what the study found, he notes.
University of Michigan’s Cooling meanwhile 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 that 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 As and Bs and undercounted Os.”
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 A-B-O finding is puzzling, we agree, and caused quite an amount of reflections and extra efforts in our group,” noting further that 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 Os are at reduced risk of infection – but not that their risk is zero.
The Chinese study, for example, found that type Os comprised about 26 per cent of Covid-19 patients, while type As made up about 34 per cent.
“You may still get severe Covid-19 with blood type O,” Karlsen says, adding: “For now, the insight of these 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, adding: “If there is any protection there, it’s going to be weak.”
A piece published in Elemental, a new Medium publication about health and wellness. Markham Heid is a health and science writer.