OA4-AM24-ST-17 - Genetic Determinants of Plasma Testosterone in Male Blood Donors Impact Red Blood Cell Characteristics and Survival in Cold Storage and After Transfusion

Non-physiological plasma concentrations of testosterone in men may reflect underlying conditions such as hypogonadism, hemochromatosis, mild anemia, and erythrocytosis. We hypothesized that dysregulation of testosterone signaling leads to ineffective male erythropoiesis, with a consequential impact on red blood cell (RBC) function and hemolysis. The aim of this study was to identify genetic polymorphisms in male donors that regulate plasma testosterone concentration and impact RBC survival in cold storage and after transfusion.

Study

Design/Methods:

This study evaluated 9 single nucleotide polymorphisms (SNPs) previously reported to be associated with testosterone deficiency or excessive testosterone in male plasma. These SNPs were linked with NHLBI’s REDS-III vein-to-vein databases to determine SNP associations with donor RBC hematological indices, percent osmotic and oxidative hemolysis in cold stored (42-day) RBCs, and RBC transfusion effectiveness defined as adjusted hemoglobin increments (delta hemoglobin, ΔHb) following a single RBC unit transfusion. To account for ancestry-specific differences in minor allele frequencies, analyses included all donor ancestry groups (trans ancestry) or ancestry-specific groups. P-values were obtained from unpaired t-tests between the two homozygous (autosomes) and hemizygous (X chromosome) alleles.

Results/Findings:

Detailed findings are summarized in Table 1. Four of the nine tested testosterone SNPs were located on the X chromosome, of which two (rs7057002, rs73629199) were significantly associated with lower RBC transfusion effectiveness (∼ -20% and -30%, respectively) compared with the reference alleles. Significant associations were observed between all testosterone SNPs and RBC osmotic fragility, susceptibility to oxidative hemolysis, and hematological indices, which are relevant to RBC transfusion effectiveness (RBC and hemoglobin concentrations). A few of the observed associations were ancestry specific affecting mostly African and Hispanic individuals. Notably, a missense mutation in the major plasma carrier of testosterone (SHBG, rs6259) was associated with significant increases in oxidative and osmotic hemolysis.

Conclusions:

Genetic determinants of plasma testosterone in male donors may significantly impact the quality and transfusion effectiveness of cold stored RBCs. Donor ancestry should be taken into consideration in such analyses given the observed differences in minor allele frequencies of testosterone SNPs. The identification of genetic variants associated with RBC transfusion effectiveness is an important step towards the development of precision transfusion medicine microarrays for enhanced screening of blood donors.