The study was led by scientists from the NHS Blood and Transplant Research Institute in Bristol, including researchers from the International Blood Group Reference Laboratory (IBGRL), in collaboration with the University of Bristol. Their discovery solves a puzzle dating back to 1972 and may help prevent dangerous transfusion reactions in a small number of patients.

Most people are familiar with the ABO and Rh blood group systems, but they represent only part of the biology of human blood. Red blood cells carry hundreds of different molecules on their surfaces. Many of these molecules act as antigens—markers that can be recognized by the immune system.

ABO and Rh compatibility are central to most blood transfusions. However, patients with rare antibodies or unusual blood types may also need blood matched for less familiar antigens.

What is the AnWj blood antigen?

The AnWj antigen was discovered in 1972, but researchers spent decades trying to determine which gene produced it and which protein carried it on red blood cells.^[1]

More than 99.9% of people are AnWj positive. For the small minority who are AnWj negative, however, the distinction can be clinically important.

If an AnWj-negative person develops antibodies against AnWj and receives AnWj-positive blood, those antibodies may attack the transfused red blood cells. In some circumstances, this can cause a potentially serious hemolytic transfusion reaction.

AnWj expression can be absent for two main reasons. In most cases, it appears to be suppressed by underlying blood diseases or certain cancers.^[2] Much more rarely, genetic changes can cause a person to be born without the antigen.

Only a handful of people with the inherited form had been identified, making the condition especially difficult to investigate.

Researchers identify the MAL gene

To search for the genetic cause, the researchers used whole-exome sequencing. This technology examines the portions of DNA that contain instructions for making proteins, allowing scientists to compare thousands of genes and look for mutations shared by affected individuals.

The analysis pointed to the MAL gene. Researchers found that people with the inherited AnWj-negative phenotype carried a homozygous deletion in MAL. Homozygous means that the relevant genetic change is present in both copies of the gene, with one copy inherited from each parent.

The MAL gene produces a small membrane protein called Mal. When the researchers examined red blood cells, they found that AnWj-positive individuals produced full-length Mal protein on their cells, while AnWj-negative cells lacked the protein.

Five genetically AnWj-negative individuals were included in the study, including a member of an Arab-Israeli family.^[3] The samples also included blood donated in 2015 by a woman who was the first person to test negative for AnWj in the 1970s.

The researchers then conducted experiments to prove that Mal was responsible for the antigen, rather than merely being associated with it.

When scientists introduced a normal MAL gene into laboratory cells, the cells became reactive with the AnWj antibody. A modified version of the gene did not produce the same response. Additional experiments showed that Mal is both necessary and sufficient for AnWj antigen expression.

MAL becomes the 47th recognized blood group system

The findings provided the evidence needed to establish MAL as a distinct blood group system, with AnWj as its defining antigen.

The International Society of Blood Transfusion formally reported MAL as ISBT 047. It was one of four blood group systems ratified during the period covered by the association’s 2026 Terminology Report, along with ER, CD36 and ATP11C.

Recognizing MAL as a blood group system means more than adding another name to a list. Researchers must connect a blood antigen to a clearly defined genetic and molecular basis before it can receive official blood group system status.

MAL was the 47th officially recognized blood group system at the time. The field has continued to expand. In September 2026, the International Society of Blood Transfusion announced JAMA as the 49th blood group system, underscoring how much remains to be learned about the genetic map of human blood.

Why the discovery matters for blood transfusions

Identifying the gene behind AnWj gives blood specialists a direct way to search for people who have inherited AnWj-negative blood.

Genotyping tests can now be developed to identify rare patients and donors with genetic changes affecting MAL. These tests could potentially be incorporated into existing blood group genotyping platforms.

This is important because compatible blood can be extremely difficult to find for people who develop antibodies against an antigen present in more than 99.9% of the population.

The concern is not merely theoretical. Previous clinical reports have shown that anti-AnWj antibodies can cause hemolytic transfusion reactions, in which transfused red blood cells are destroyed by the recipient’s immune system.

Recent cases show the complexity of anti-AnWj antibodies

In 2026, researchers reported a 75-year-old man with severe anemia and anti-AnWj autoantibodies. Because compatible blood was unavailable, doctors weighed the risks and ultimately transfused incompatible red blood cells. Genetic testing showed that his MAL genes were normal, supporting the conclusion that his antibodies had been acquired rather than caused by an inherited MAL defect. He did not experience a hemolytic transfusion reaction.

Another 2026 case involved a patient with high-grade B-cell lymphoma and complement-fixing anti-AnWj autoantibodies. After signs of red blood cell destruction developed following an incompatible transfusion, clinicians used stimulimab, a drug that blocks part of the immune complement pathway.

Although the patient’s laboratory tests improved, the researchers emphasized that the complexity of the case and the short treatment period prevented firm conclusions about the drug’s effectiveness. It was the first reported use of stimulimab for this specific type of anti-AnWj-associated hemolysis.

Together, these cases highlight an important distinction. Some people are AnWj negative because of inherited changes in MAL. Others lose AnWj expression because of disease and may develop antibodies against a marker that was previously present on their own cells.

A 50-year mystery solved through genetic testing

Louise Tilley, Senior Research Scientist at the IBGRL Red Cell Reference Laboratory, NHS Blood and Transplant, said:

“The genetic background of AnWj has been a mystery for more than 50 years, and it is a problem that I have personally been trying to solve for almost 20 years of my career. It is a major achievement and the culmination of a long team effort to finally establish this new blood group system, allowing us to provide the best care to this rare but important patient.”

“The study was difficult because the genetic cases are so rare. We could not have achieved this without exome sequencing, as the gene we identified is not a clear candidate and little is known about the Mal protein in red blood cells. It has been difficult to prove our findings, but we would like to thank all our collaborators and patients for their help.”

The mystery persisted partly because inherited AnWj-negative blood is exceptionally rare. With so few known cases, researchers had limited genetic material from affected individuals to compare.

The Mal protein also offered few obvious clues. It is a very small protein embedded in cell membranes and is involved in membrane organization and cellular transport. Nothing initially indicated that it carried the long-mysterious AnWj antigen on red blood cells.

Gene editing helped confirm the discovery

Ash Toy, Professor of Cell Biology in the School of Biochemistry and Director of the NIHR Blood and Transplant Research Unit for Red Blood Cell Products at the University of Bristol, said:

“It is truly exciting that we have been able to harness the ability to manipulate gene expression in developing blood cells to help confirm the identity of the AnWj blood group, which has been a prominent mystery for half a century. This development will help identify these rare donors and help patients in the future.”

By manipulating gene expression, the researchers were able to study cause and effect instead of simply observing that a genetic variation occurred in AnWj-negative people. When they changed which genes cells expressed and tested whether AnWj appeared, they strengthened the evidence that MAL was the missing link.

Nicole Thornton, Head of the IBGRL Red Cell Reference Laboratory at NHS Blood and Transplant, said:

“Unraveling the genetic basis of AnWj is one of our most challenging projects.”

“It will take a significant amount of research to prove that genes do in fact encode blood group antigens, which is why we are passionate about making these discoveries for the benefit of rare patients around the world.”

“We can now design genotyping tests to identify patients and donors who are genetically negative for AnWj. Such tests can be added to existing genotyping platforms.”

The official ISBT blood group database lists the reference MAL allele along with the null allele associated with the AnWj-negative phenotype. This transforms AnWj from an unexplained serological curiosity into a genetically defined blood group system.

Human blood is far more complex than ABO and Rh

The story of MAL illustrates the complexity hidden behind the familiar blood types A, B, AB and O.

Blood groups are defined by genetic differences in molecules found on red blood cells. These differences often have little noticeable effect in everyday life, but they can become important when the immune system encounters red blood cells carrying antigens it recognizes as foreign—particularly during transfusions and pregnancy.

Research into rare blood groups can therefore have a significant clinical impact even when it involves only a few participants. If a patient has antibodies against an antigen found in almost everyone, locating compatible donor blood may require specialized laboratories, rare-donor registries and international cooperation.

Dr Tim Satchwell, Research Fellow at the University of Bristol and Senior Lecturer at UWE Bristol, said:

“Mal is a very small protein with some interesting properties, making it difficult to identify and requiring multiple studies to accumulate the evidence needed to establish this blood group system. It was a huge satisfaction for the whole team to finally be able to combine our expertise to achieve this.”

For more than 50 years, AnWj was a blood antigen with no known genetic origin. Identifying MAL provides a molecular explanation, creates a path toward improved genetic testing and increases the chance that difficult blood-matching cases can be identified before they become emergencies.

Key facts about the MAL and AnWj blood group system

• ABO and Rh are the two best-known blood group systems, but human blood contains many additional antigens.
• There are currently 47 recognized blood group systems containing more than 360 recognized blood antigens.
• AnWj is present in more than 99.9% of people.
• AnWj is named after the people who first produced the antibody: Anton and Wj.
• Disease can suppress Mal expression and make a patient AnWj negative.
• A rare inherited deletion in both copies of the MAL gene can also result in AnWj-negative blood.
• People who are genetically AnWj negative are healthy.
• Genotyping tests may help identify rare AnWj-negative patients and donors for safer transfusion matching.