It’s a question that has been vexing researchers for more than half a century but have yet to fully answer: Does having a certain blood type—AB or O, for example—increase your risk for heart disease?

Some patients may not even know this is being asked. After all, it’s believed many Americans don’t know their blood type, so any health risks associated with it wouldn’t likely be on their minds. But a quick Google search reveals loads of studies, including ones led by Penn Medicine researchers, investigating a possible connection—and those are just the ones over the last year.

Indeed, scientists have been trying to better understand the relationship between disease and blood type since the early 1900s, when they first discovered that antibodies and antigens on blood cells and plasma are inherited. Heart disease risk became more into focus in the late 1960s, and clearer in the 1970s when results from the Framingham Heart Study, a large, ongoing study designed in the 1940s to answer much-needed questions about the cause and prevention of heart disease, were published. In the following years, researchers continued to study both small and large groups of patients for extended periods to see who may develop such diseases.

Here’s one finding that has continued to surface over the years: People with a non-O blood type (that’s A, B, or AB) are at a higher risk of developing cardiovascular diseases. Exactly why this is remains unknown, but many speculate that it may have to do with something called the von Willebrand factor, a protein associated with clotting that’s found in greater concentrations in the non-O blood types, or potentially higher cholesterol levels associated with blood types.

Blood is divided into four groups—A, B, AB, and O—which are determined based on the presence or absence of antigens in red blood cells. In addition to the A and B antigens, there is a third antigen known as the Rh factor used to name types. So, for example, if someone is blood type A but lacks the Rh factor, they are A negative. Worth noting is that about half the population is type O, meaning the other half have either A, B, or AB.

Now, how big a risk blood types pose and the significance of that risk has been more debated among researchers.

That first study in the mid-1970s from the Framingham cohort described a “slight excess risk of [cardiovascular disease] for non-O men, although this conclusion is tentative due to lack of statistical significance.” By the 1980s and 1990s, more studies had surfaced and solidified the risk in the non-O group, but findings were still uneven. Blood type A positive was associated with an increased risk over the others in many reports, and the risks for the non-O group were being reported as slight to significant, depending on the group of people being studied (gender, ethnicity, etc.) and how big a cohort.

Fast forward to times closer to now, and the risk remains, as well as some inconsistency in the findings.

A 2012 study in the journal Arteriosclerosis, Thrombosis and Vascular Biology that included more than 20 years of data from 62,000 women and 27,000 men found that blood type AB was associated with a 23% higher risk of cardiovascular disease, while type B was associated with an 11% higher risk, compared to O type. The overall risk was 6.27%.

Last May, at the 2017 Heart Failure meeting in Paris, researchers presented data on more than a million patients and found that people with type A, B, or AB blood were 9% more likely to have a cardiovascular event than those with type O blood.

Penn researchers have also investigated the link and found mixed results. In December 2017, at the annual meeting of the American Society of Hematology (ASH) in Atlanta, Penn and Thomas Jefferson University researchers presented new data from the Framingham Heart Study. This was a prospective study of over 4,000 patients without prior cardiovascular events.

“The Framingham study has a lot of advantages: it’s large, and it has a long follow-up period—38 years,” said Stephen Kimmel, MD, MSCE, director of Cardiovascular Epidemiology in the department of Medicine at Penn and Center for Clinical Epidemiology and Biostatistics, and senior author on the ASH abstract. “It has incredibly rich information about other cardiac risk factors, factors that one would want to examine to ensure the effects of a blood group, if there was one, were independent of additional cardiac risk factors.”

Interestingly, the researchers found no association between blood type and heart disease in that group. However, when they expanded it to five other cohorts from previous studies, a risk was evident. Those with a non-O blood type were at a 12% increased risk for cardiovascular events.

So, there’s a risk in the research, but what does all this mean for patients today?

Right now, not much. There isn’t enough information to move this to the list of risk factors that physicians discuss with their patients like age, cholesterol, nicotine habits, or blood pressure, researchers have said.

“We haven’t put it to rest,” Kimmel said. “I think what it suggests is that if there is an effect of blood type, it is probably pretty small, and not nearly as consequential as having, for example, diabetes.”

A person can’t change their blood type, but they can change their behavior, quit smoking, or exercise more to reduce their risk for heart diseases. This is what patients should be focusing on to help prevent heart diseases, Kimmel said.

Still, that doesn’t rule blood type out as a potential risk factor worth discussing in the future. The non-O blood group could be considered when evaluating risk factors for primary prevention for disease, as more studies shine light on this relationship, Kimmel added.

“There are perhaps other things that need to be further explored about how blood group alters propensity for cardiac disease,” he said. “Or, maybe if one can get a better handle on a biomarker related to the mechanism, that might be a more powerful method of predicting future cardiovascular events.”

Daniel Levy, MD, director of the Framingham Heart Study, and medical officer of the National Heart, Lung, and Blood Institute, had this to say, as reported in a 2013 commentary on the topic, for patients who ask their physicians about blood type concerns: “Your blood type will be most important on the day you need a transfusion.”

Kimmel agreed, adding: “It’s this interesting idea that people have had for decades, but I think the bottom line is that it is still just that. It’s not ready for prime time use in the clinics.”