Genetic determinants of plasma testosterone in male blood donors are associated with altered red blood cell characteristics and survival in cold storage and after transfusion

Genetic mutations in genes regulating plasma testosterone in men may interfere with effective erythropoiesis, and may result in red blood cell (RBC) dysfunction and hemolysis. The aim of this study was to identify genetic polymorphisms in male donors that regulate plasma testosterone and impact RBC survival in cold storage and after transfusion. We evaluated nine single nucleotide polymorphisms (SNPs) previously reported to be associated with circulating testosterone in male plasma. These SNPs were linked with donor-component-recipient databases (NIH REDS program) to determine SNP associations with donor RBC hematological indices, osmotic and oxidative hemolysis, and RBC transfusion effectiveness defined as adjusted hemoglobin increments (delta hemoglobin, ΔHb) following a single RBC unit transfusion. Four of the nine testosterone SNPs were located on the X chromosome, of which two (rs7057002, rs73629199) were significantly associated with reduced hemoglobin increments (0.2 and 0.3 g/dL, respectively) compared with reference alleles in transfused recipients. Seven of the nine testosterone SNPs were associated with significant changes in RBC susceptibility to osmotic hemolysis including a missense mutation in the major plasma carrier of testosterone (SHBG, rs6259), and four SNPs with changes in oxidative hemolysis. Four SNPs were associated with decreased RBC count, hemoglobin, and hematocrit. Ancestry/ethnicity-specific (African and Hispanic) associations were observed between two SNPs (rs7057002, rs7879462) and oxidative hemolysis. Genetic determinants of plasma testosterone in male donors significantly impact the quality and transfusion effectiveness of cold stored RBCs. Testosterone SNPs associated with decreased RBC transfusion effectiveness may have clinical implications and warrant further revaluation.