A Breakthrough in Blood Type Research

A long-standing quest to understand a mysterious blood antigen has finally led scientists to uncover a hidden genetic difference in a very small number of individuals.

After over five decades of research, experts have cracked the enigma of the rare AnWj blood group. This discovery could significantly enhance the safety of blood transfusions for patients globally.

Researchers from the UK and Israel have pinpointed the genetic factor behind the AnWj blood group, resulting in the establishment of a completely new blood group system known as MAL. Not only does this resolution bring a long-standing scientific inquiry to a close, but it also paves the way for better screening for individuals with extremely rare blood types who could suffer severe transfusion reactions.

The study was spearheaded by NHS Blood and Transplant through its International Blood Group Reference Laboratory (IBGRL) in Bristol, with help from the University of Bristol and various international partners. The findings were published in the journal Blood, associated with the American Society of Hematology.

The Complexity Beyond ABO Blood Types

Most people are familiar with their blood types being A, B, AB, or O, along with the Rh factor indicating positive or negative status. However, these familiar categories only scratch the surface of human blood diversity.

Currently, scientists have identified 47 distinct blood group systems that contain over 360 different blood antigens. These antigens, found on red blood cells, can provoke serious immune reactions due to even minor discrepancies between donors and recipients.

The newly established MAL blood group system focuses on the AnWj antigen, a rare marker first identified in 1972. The name “AnWj” derives from the initial patients who produced the antibody, Anton and Wj.

For more than half a century, while researchers could detect the antigen’s presence, they were unable to identify which gene was responsible for it.

Solving a Medical Mystery

Using whole exome sequencing—which examines all protein-coding DNA regions—researchers discovered that those who are AnWj-negative possess deletions in both copies of the MAL gene. This gene creates a tiny membrane protein called Mal, which is crucial for maintaining cell membrane stability and facilitating transport.

The study revealed that individuals with normal AnWj-positive blood express the full-length Mal protein on their red blood cells, whereas AnWj-negative individuals do not.

To validate their finding, scientists introduced the normal MAL gene into blood cell lines in the laboratory, leading those cells to produce the AnWj antigen. Mutated versions of the gene were ineffective, providing robust evidence that the Mal protein is essential for this blood group.

Why This Matters

Interestingly, over 99.9% of the population is AnWj-positive, but for the small minority who are AnWj-negative, receiving incompatible blood can provoke severe reactions.

Identifying these individuals has been challenging due to the previously unknown genetic basis. However, the new discovery could lead to the development of genetic tests aimed at pinpointing rare donors and patients prior to transfusions. Researchers anticipate that these tests may eventually be incorporated into current blood typing methods.

This matter becomes even more significant as many AnWj-negative cases aren’t passed down genetically. Conditions such as blood disorders and cancers can temporarily suppress the Mal protein, causing individuals to appear AnWj-negative even without the rare genetic makeup.

The inherited version is exceedingly rare, with the study noting only five cases, including those in an Arab-Israeli family. There could be more unrecognized instances worldwide now that testing options have been established.

Importantly, those born with the inherited MAL deletion are generally in good health.

A Milestone Discovery

This breakthrough was possible thanks to advances in DNA sequencing technology, which weren’t available when the AnWj antigen was first discovered.

Louise Tilley, a Senior Research Scientist at NHS Blood and Transplant, dedicated nearly 20 years to unraveling this mystery. “The genetic background of AnWj has been enigmatic for over 50 years, and I’ve personally aimed to solve it for almost two decades. This achievement showcases a significant team effort,” Tilley shared.

Ash Toye, a Professor of Cell Biology at the University of Bristol, emphasized that modern genetic tools are drastically changing transfusion medicine: “It’s thrilling to see how we used gene expression manipulation in developing blood cells to clarify the AnWj blood group, a puzzle that has lingered for half a century.”

The discovery has been officially recognized by the International Society of Blood Transfusion (ISBT), which has ratified MAL as the 47th official blood group system worldwide.

Importance of Rare Blood Research

Although rare blood types affect a small portion of the population, their identification has become crucial as medicine evolves toward greater personalization and global interconnectedness.

Patients with rare blood types often depend on specifically matched donors, which can even require finding individuals from other countries. Worldwide blood banks maintain rare donor registries to help secure compatible blood during urgent situations or diverse medical procedures.

Researchers argue that findings like those related to MAL continue to diminish the number of unexplained blood antigens in medicine, enhancing transfusion safety and deepening our understanding of human genetics.