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Overview

Subsequent to its ancient origin in Africa, the sickle hemoglobin (HbS) gene spread to the Western Hemisphere, Europe, the Middle East, and the Indian subcontinent by slave trading, war, and migration (Figure 1-1). The phenotype of sickle cell disease is caused by several common and many rare genotypes. All have in common at least 50% HbS in the blood. Among these genotypes, the most frequent and severe clinically is homozygosity for the HbS gene (HbSS or sickle cell anemia), followed by compound heterozygosity for the HbS and the hemoglobin C (HbC) gene (HbSC disease) and compound heterozygosity for HbS and various β thalassemia genes (HbS-β thalassemia). The HbS gene is associated with 5 common β-globin gene haplotypes, named after regions of high gene frequency in Africa, the Middle East, and India. These haplotypes have a loose association with the severity of disease that is explained by the characteristic fetal hemoglobin (HbF) level of each haplotype. HbF is the major modulator of the phenotype of sickle cell disease; it inhibits the polymerization of HbS that initiates the pathophysiology of disease, and it also dilutes the intraerythrocytic HbS concentration, a key factor in the sickling kinetics. Because HbS polymerization is the key mechanism that triggers all other pathophysiologic events, preventing polymerization has been of prime therapeutic interest. Decades have been devoted to understanding how the HbF genes are almost totally turned off after birth and whether and how this switch from fetal to adult hemoglobin gene expression can be reversed by drugs or cellular therapeutics. In this chapter, we prepare the reader for understanding the pathophysiologic basis of the complications of sickle cell disease and the future therapeutic landscape by discussing the origin and genetic background of the HbS mutation, the most common genotypes of this disease, the regulation of gene expression within the globin gene clusters, and genetic variants that might explain disease heterogeneity.

FIGURE 1-1

World distribution of sickle cell anemia with expected numbers of newborns. Adapted from Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. 2017;376:1561-1573. doi:10.1056/NEJMra1510865.

Evolution and Structure of Human Hemoglobin

Billions of years of evolution have morphed ancient protein motifs that functioned in bacteria and protists as electron transporters and nitric oxide (NO) dioxygenases to human hemoglobin that transports oxygen and metabolizes NO.1 The aboriginal, primitive monomeric protein has become a heterotetrameric protein encoded in 2 nonallelic gene clusters and provides an essential function of vertebrate life (Figure 1-2). Homozygosity or compound heterozygosity for a single mutation in the gene encoding one of the hemoglobin subunits, the β-hemoglobin gene (HBB; rs334, GAG-GTG; β7 glu-val; E7V; MIM 603903), is found in all individuals with sickle cell disease. Via complex pathophysiologic paths, beginning with its polymerization, HbS leads to the many ...

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