Genome-wide association study of erythrocyte density in sickle cell disease patients.

Deoxy-hemoglobin S polymerization into rigid fibers is the direct cause of the clinical sequelae observed in sickle cell disease (SCD). The rate of polymerization of sickle hemoglobin is determined primarily by intracellular hemoglobin concentration, itself dependent on the amount of sickle hemoglobin and on red blood cell (RBC) volume. Dense, dehydrated RBC (DRBC) are observed in SCD patients, and their number correlates with hemolytic parameters and complications such as renal dysfunction, leg ulcers and priapism. To identify new genes involved in RBC hydration in SCD, we performed the first genome-wide association study for DRBC in 374 sickle cell anemia (HbSS) patients. We did not find genome-wide significant results, indicating that variants that modulate DRBC have modest-to-weak effects. A secondary analysis demonstrated a nominal association (P=0.003) between DRBC in SCD patients and a variant associated with mean corpuscular hemoglobin concentration (MCHC) in non-anemic individuals. This intronic variant controls the expression of ATP2B4, the main calcium pump in erythrocytes. Our study highlights ATP2B4 as a promising target for modulation of RBC hydration in SCD patients.

Approaches for Analysis of Erythroid Cell Parameters and Hemoglobinopathies in Mouse Models.

Over the last decades several mouse models of human hemoglobin disorders have been and continue to be generated. This chapter aims at describing various approaches to evaluate the global red blood cell properties in mouse models of human hemoglobin disorders, in particular thalassemia and sickle cell disease. Analysis of erythroid parameters provides insights into the RBC physiologic or pathophysiologic status. Mice expressing both murine and human globin genes can be investigated using adapted protocols provided herein.