Kudos to the amazing work by @grkeele.bsky.social at RTI International, Gary Churchill @jacksonlab.bsky.social and Jim Zimring at Canadian Blood Services

STEAP3 variation also mapped to several apolipoproteins (including APOA1, APOC3, APOE), linking RBC iron handling to lipid oxidation and vesiculation pathways, potentially bridging neurodegenerative disease biology to RBC iron metabolism with systemic oxidative stress.

This work also represents, to our knowledge, the first pQTL + PTM-QTL map in an enucleated cell type, showing how genetic differences established during erythropoiesis continue to shape the mature RBC proteome through redox and degradative pathways.

A second locus, Steap3, influenced the oxidation of lipids and proteins, vesiculation-related proteins (including several apolipoproteins), and storage-related hemolysis.
Higher Steap3 activity correlated with greater oxidative stress and lower post-transfusion recovery.

We used humanized mice expressing either canonical human HBB or a C93A variant.
Loss of βCys93 altered glutathione balance, increased oxidative modifications, changed proteolytic signatures, and reduced post-transfusion recovery.
These effects align with predictions from the genetic mapping.

The Hbb locus was particularly influential.
Certain founder strains carry an additional cysteine at β13, while others carry only the conserved β93 cysteine.
Variation at these positions was associated with widespread differences in oxidative PTMs and glutathione-related chemistry.

Four loci accounted for much of this trans-regulation:
• Hbb (β-globin)
• Hba (α-globin)
• Steap3 (ferrireductase involved in iron handling)
• Mon1a (vesicular trafficking / iron recycling)

We identified over 6,000 QTLs, with a predominance of trans-acting effects, opposite to nucleated tissues, where cis-pQTLs tend to dominate.
In RBCs, absence of transcription shifts regulatory influence toward genetic effects that modify redox state and protein turnover.

Unlike most tissues, RBCs cannot synthesize new proteins.
This makes them an informative system in which to study post-translational regulation, proteolysis, and oxidative damage.
We quantified proteins, peptides, and 20+ PTM types in both fresh and stored RBCs (blood bank mimicking conditions).

Thank you, Thomas!

Congratulations!