Genetic variation of human G6PD impacts Red Blood Cell transfusion efficacy

Karafin, M. S.; Issaian, A. V.; Bevers, S.; Reisz, J. A.; Hay, A.; Keele, G. R.; Dzieciatkowska, M.; Cendali, F. I.; Haiman, Z. B.; Key, A. M.; Nemkov, T.; Stephenson, D.; Marsh, E.; Moore, A.; Palha, M. S.; Legenzov, E. A.; Lamb, D. R.; Deng, X.; Stone, M.; Hansen, K.; Kleinman, S.; Norris, P. J.; Busch, M. P.; Vallese, F.; Palsson, B. O.; Spitalnik, S.; Kao, J. P.; Roubinian, N. H.; Janetzko, J.; Page, G. P.; Eisenmesser, E. Z.; Zimring, J. C.; Buehler, P. W.; D'Alessandro, A.

doi:10.1101/2025.11.21.689741

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bioRxiv · 10.1101/2025.11.21.689741

Genetic variation of human G6PD impacts Red Blood Cell transfusion efficacy

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Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common human enzymopathy, affects 6% of the global population, yet its impact on blood storage and transfusion efficacy remains undefined. We integrated genome-metabolome-proteome analyses of 13,091 blood donors (362 G6PD SNPs), validated in a recalled cohort (n=643), linked donor-recipient databases, humanized mouse models (canonical, African A- [V68M+N126D], Mediterranean [S188F]), and a prospective sickle cell disease study. Common G6PD variants reduced protein abundance, reprogrammed redox metabolism, and increased storage hemolysis. In mice, G6PD-deficient RBCs showed lower post-transfusion recovery, higher oxidative stress, and impaired renal oxygenation. Clinically, recipients of G6PD-deficient units exhibited smaller hemoglobin increments and reduced RBC L{superscript 1}Cr-survival (-8% at 24 h; -12% at 4 weeks). Structural studies revealed kinetic fragility for A- and thermodynamic fragility for Med-, linking genotype to protein instability and transfusion outcome. These findings identify donor G6PD genotype as a determinant of transfusion efficacy, supporting genotype-aware inventory-management strategies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/689741v1_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@1897489org.highwire.dtl.DTLVardef@1420587org.highwire.dtl.DTLVardef@178e8ddorg.highwire.dtl.DTLVardef@1003b44_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Karafin, M. S., Issaian, A. V., Bevers, S., Reisz, J. A., Hay, A., Keele, G. R., Dzieciatkowska, M., Cendali, F. I., Haiman, Z. B., Key, A. M., Nemkov, T., Stephenson, D., Marsh, E., Moore, A., Palha, M. S., Legenzov, E. A., Lamb, D. R., Deng, X., Stone, M., Hansen, K., Kleinman, S., Norris, P. J., Busch, M. P., Vallese, F., Palsson, B. O., Spitalnik, S., Kao, J. P., Roubinian, N. H., Janetzko, J., Page, G. P., Eisenmesser, E. Z., Zimring, J. C., Buehler, P. W., D'Alessandro, A.. 2025-11-22. Genetic variation of human G6PD impacts Red Blood Cell transfusion efficacy. https://doi.org/10.1101/2025.11.21.689741

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