FY1: The Door Malaria Knocked On

If you’ve worked in a blood bank long for any amout of time, you’ve probably seen an anti-Fyᵃ or two show up in an antibody panel. It’s one of those “frequent flyers” that gets respect in serology but doesn’t always get the spotlight it deserves. Yet, behind that simple reaction at AHG lies one of the most fascinating stories in human genetics — a blood group system whose absence changed the way humans survived malaria.

The Science Behind the Name

FY1, belongs to the Duffy blood group system (ISBT 008). It’s encoded by the FY*A allele of the Atypical Chemokine Receptor 1 (ACKR1). This gene name tells you almost everything you need to know about its personality. ACKR1 looks like a G protein–coupled receptor, the kind that normally sends intracellular messages when it binds to a molecule. But Duffy doesn’t do that. It’s “atypical” because it doesn’t signal through G-proteins at all. Instead, it acts as a decoy receptor or chemokine sponge — grabbing onto pro-inflammatory chemokines and helping to keep inflammation under control.

This same protein is expressed not only on red cells, but also on endothelial cells lining the small blood vessels throughout the body.

The Malaria Connection

Now here’s where things get really interesting. That same Duffy protein that helps regulate inflammation also happens to be the receptor that Plasmodium vivax, one of the major malaria parasites, uses to invade red blood cells. The parasite’s Duffy-binding protein recognizes Duffy like a key fits a lock. Once it binds, it slips inside the cell, multiplies, and continues the infection cycle.

But not everyone gives malaria that opportunity. People who lack both Fyᵃ and Fyᵇ antigens on their red cells, the Fy(a–b–) or Duffy-null phenotype, don’t express the Duffy protein on their red cells at all. For P. vivax, that means no door, no entry. These individuals are naturally resistant to P. vivax malaria.

A Tiny Change with Big Consequences

At the molecular level, Fyᵃ and Fyᵇ differ by just one amino acid: glycine in Fyᵃ and aspartic acid in Fyᵇ. In serologic testing, anti-Fyᵃ is a clinically significant IgG antibody, usually of the IgG1 or IgG3 subclass, reacting best at the AHG phase. It’s destroyed by ficin, papain, and DTT, and it can cause delayed hemolytic transfusion reactions (DHTRs) and mild hemolytic disease of the fetus and newborn (HDFN).

Because of antigen frequency differences between populations, anti-Fyᵃ is far more common in patients of African ancestry (where Fyᵃ is relatively rare) and much less frequent in Caucasians (where Fyᵃ is common). Fyᵃ-negative donors make up about 10% of Black populations but only about 34% of Caucasians.