Researchers discover new blood group system

The discovery of a new blood group, MAL, has solved a 50-year-old mystery. Researchers from NHS Blood and Transplant (Bristol), NHSBT's International Blood Group Reference Laboratory (IBGRL) and the University of Bristol have identified the genetic background of the previously known but mysterious AnWj blood group antigen. The discovery has made it possible to identify and treat rare patients with this blood group deficiency.

Some people do not have this blood type due to disease, but a rare inherited form of the AnWj-negative phenotype has only been found in a few individuals — although this discovery should make it easier to find others in the future.

The two most well-known blood group systems are ABO and Rh, but blood is more complex, and matching between other groups can be lifesaving.

AnWj-negative people may have a transfusion reaction if they are given AnWj-positive blood, and this research allows for the development of new genotyping tests to detect such rare individuals and reduce the risk of transfusion-associated complications.

The AnWj antigen – an antigen is a surface marker – was discovered in 1972 but its genetic background was unknown until now. New research published in BloodEstablishes a new blood group system (MAL), the 47th system discovered so far, which is home to the ANWJ antigen.

The research team found that AnWj is carried on the Mal protein. More than 99.9% of people are AnWj-positive, and such individuals were shown to express the full-length Mal protein on their red cells, which was not present on the cells of AnWj-negative individuals. The team identified homozygous deletions in the MAL gene associated with the inherited AnWj-negative phenotype.

The most common reason for being AnWj-negative is suffering from a hematological disorder or certain types of cancer that suppress antigen expression. A small number of people are AnWj-negative for genetic reasons. The study included five genetically AnWj negative individuals, including a family of Arab-Israelis. The blood tested included a sample donated in 2015 by a woman who was the first AnWj negative person to be discovered in the 1970s.

The research team used whole exome sequencing – genetic sequencing of all the DNA that codes for proteins – to show that these rare inherited cases were caused by homozygous DNA sequence deletions in the MAL gene, which codes for the MAL protein.

Evidence that Mal is responsible for the binding of AnWj antibodies isolated from these rare patients was provided by experiments that showed the presence of specific reactivity with cells that the researchers used to express the normal MAL gene but not the mutant gene.

Louise Tilly, senior research scientist for IBGRL Red Cell Reference at NHS Blood and Transplant, said: “The genetic background of ANWJ has been a mystery for over 50 years, and one that I have personally been trying to solve for almost 20 years of my career. This is a huge achievement, and the culmination of a long team effort, to finally be able to establish this new blood group system and provide the best care possible for rare, but vital patients.

“This work was difficult because genetic cases are so rare. We would not have been able to achieve this without exome sequencing, as the gene we identified was not an obvious candidate and little is known about the cargo protein in red blood cells. Proving our findings was challenging, and we are grateful for the help of all our colleagues and patients, without whom we would not have been able to reach this point.”

Ash Toy, Professor of Cell Biology in the School of Biochemistry at the University of Bristol and Director of the NIHR Blood and Transplant Research Unit in Red Blood Cell Products, said: “It's really exciting that we were able to confirm the identity of the AnWj blood group using our ability to manipulate gene expression in developing blood cells, which had been a puzzle for half a century. This development will help to identify these rare donors and help patients in the future.”

Nicole Thornton, Head of IBGRL Red Cell Reference at NHS Blood and Transplant, said: “Unravelling the genetic basis of ANWJ has been one of our most challenging projects.

“It takes a lot more work to prove that a gene actually encodes a blood group antigen, but we are very excited that we are making these discoveries for the benefit of rare disease patients around the world.

“Genotyping tests can now be designed to genetically identify AnWj-negative patients and donors. Such tests could be added to existing genotyping platforms.”

Dr Tim Satchwell, Senior Lecturer at UWE Bristol, who contributed to the study as a Research Fellow at the University of Bristol, said: “Mal is a very small protein with some interesting properties, which made it difficult to identify and meant we had to carry out a number of different investigations to gather the evidence we needed to establish this blood group system. It has been very satisfying for the whole team to be able to combine our expertise to finally achieve this goal.”