According to standard tests, two people with blood type A are considered identical. However, their red blood cells can show great differences. This disparity, long a mystery for transfusion medicine, has finally been elucidated.
In reality, blood type is not limited to the letters A, B, AB, or O. It also depends on the number of antigens present on the surface of red blood cells. These antigens are molecules that the immune system uses to distinguish 'self' from 'foreign'. Until now, the genes that produce these antigens were known, but not why their quantity varies so much from one person to another for the same blood type.
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To solve this problem, researchers at Lund University in Sweden looked beyond the genes themselves and focused on their regulation. They targeted transcription factors, proteins that act as molecular switches by binding to specific DNA regions to control gene expression.
Thanks to a new computer tool developed by doctoral student Gloria Wu, the team mapped nearly 200 binding sites for transcription factors on 33 blood group genes. This approach made it possible to predict where gene activity could be modified, something that classic genetic tests do not show.
The researchers then tested their method on a particularly troubling case: the Helgeson blood group. Present in about 1% of the population, this rare variant is characterized by abnormally low levels of CR1, a protein involved in immune defense. Its genetic cause remained unknown, and even DNA tests struggled to identify it.
The new analysis revealed that the Helgeson variant is caused by a tiny change in a DNA sequence where a transcription factor should bind. Since the protein cannot attach properly, the CR1 gene is only weakly activated, which reduces the amount of the molecule on the surface of red blood cells. As Martin L Olsson, professor of transfusion medicine, explains, 'the gene then runs at low speed.'
This discovery also showed that the Helgeson variant is more common among Thai blood donors than Swedish donors. This is explained by the fact that a low level of CR1 protects against malaria, a parasitic disease very prevalent in Southeast Asia. Thus, a trait that complicates transfusion tests offers an evolutionary advantage in regions where malaria is rampant.
Malaria parasites have more difficulty penetrating red blood cells that carry little CR1. 'Thanks to what we now know, we can improve laboratory tests,' says Gloria Wu. The team plans to update the DNA chip used for blood groups by including this new variant, which will make diagnosis safer.