Innate Variability in Physiological and Omics Aspects of the Beta Thalassemia Trait-Specific Donor Variation Effects

Abstract

The broad spectrum of beta-thalassemia (βThal) mutations may result in mild reduction (β++), severe reduction (β+) or complete absence (β0) of beta-globin synthesis. βThal heterozygotes eligible for blood donation are “good storers” in terms of red blood cell (RBC) fragility, proteostasis and redox parameters of storage lesion. However, it has not been examined if heterogeneity in genetic backgrounds among βThal-trait donors affects their RBC storability profile. For this purpose, a paired analysis of physiological and omics parameters was performed in freshly drawn blood and CPD/SAGM-stored RBCs donated by eligible volunteers of β++ (N = 4), β+ (N = 9) and β0 (N = 2) mutation-based phenotypes. Compared to β+, β++ RBCs were characterized by significantly lower RDW and HbA2 but higher hematocrit, MCV and NADPH levels in vivo. Moreover, they had lower levels of reactive oxygen species and markers of oxidative stress, already from baseline. Interestingly, their lower myosin and arginase membrane levels were accompanied by increased cellular fragility and arginine values. Proteostasis markers (proteasomal activity and/or chaperoning-protein membrane-binding) seem to be also diminished in β++ as opposed to the other two phenotypic groups. Overall, despite the low number of samples in the sub-cohorts, it seems that the second level of genetic variability among the group of βThal-trait donors is reflected not only in the physiological features of RBCs in vivo, but almost equally in their storability profiles. Mutations that only slightly affect the globin chain equilibrium direct RBCs towards phenotypes closer to the average control, at least in terms of fragility indices and proteostatic dynamics.

Sickle Cell Hemoglobin Genotypes Affect Malaria Parasite Growth and Correlate with Exosomal miR-451a and let-7i-5p Levels

“…This is supported by previous research indicating that oxygen plays a role in malaria resistance [36]. Moreover, studies examining the impact of the beta-thalassemia trait on redox equilibrium and cytoskeleton structure, depending on the severity of the mutation, suggest that similar differences may exist between sickle cell Hb genotypes [37]. Given that oxidative stress and cytoskeleton features have been linked to malaria resistance, it is possible that these genotype-related differences may also play a role in sickle cells' protective effects against malaria [38,39].…”

Decrease in α-Globin and Increase in the Autophagy-Activating Kinase ULK1 mRNA in Erythroid Precursors from β-Thalassemia Patients Treated with Sirolimus

“…As p62 is involved in both autophagy and proteasome activity [31,32], this issue should be carefully analyzed in the future. In this respect, proteasome has been suggested to be implicated in decongesting erythroid precursors and mature red blood cells from excess hemoglobin [33][34][35]. This observation reinforces the interest in analyzing the effects of sirolimus on proteasome [36,37].…”

Red Blood Cell Metabolism In Vivo and In Vitro

“…Since HPRT (see above) is an X-linked gene, sex dimorphisms in this pathway are observed in the stored RBCs [ 48 ]. One additional confounder related to sex pertains to the relative age of circulating RBCs at the time of donation, generally younger in pre-menopausal females [ 160 ], further confirming a sex dimorphism in RBC storability [ 161 ]. Indeed, small-scale studies have demonstrated RBC storability differences in the hemolytic propensity and membrane binding of stress protein markers between pre- and post-menopausal women [ 162 , 163 ].…”