Genetic variation of human G6PD impacts Red Blood Cell transfusion efficacy.

Pubmed ID: 41332617

Pubmed Central ID: PMC12667890

Journal: bioRxiv : the preprint server for biology

Publication Date: Nov. 22, 2025

Grants: T32 HL007171

Authors: Busch MP, Kleinman S, Deng X, Norris PJ, Page GP, Roubinian NH, Spitalnik SL, Reisz JA, Nemkov T, Stephenson D, Keele GR, Dzieciatkowska M, Hansen KC, Zimring JC, D'Alessandro A, Hay A, Haiman ZB, Stone M, Palsson BO, Key AM, Bevers S, Moore AL, Karafin MS, Issaian AV, Cendali FI, Marsh E, Palha MS, Legenzov EA, Lamb DR, Vallese F, Kao JPY, Janetzko J, Eisenmesser EZ, Buehler PW

Cite As: Karafin MS, Issaian AV, Bevers S, Reisz JA, Hay A, Keele GR, Dzieciatkowska M, Cendali FI, Haiman ZB, Key AM, Nemkov T, Stephenson D, Marsh E, Moore AL, Palha MS, Legenzov EA, Lamb DR, Deng X, Stone M, Hansen KC, Kleinman S, Norris PJ, Busch MP, Vallese F, Palsson BO, Spitalnik SL, Kao JPY, Roubinian NH, Janetzko J, Page GP, Eisenmesser EZ, Zimring JC, Buehler PW, D'Alessandro A. Genetic variation of human G6PD impacts Red Blood Cell transfusion efficacy. bioRxiv 2025 Nov 22.

Studies:

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 L¹Cr-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.