![]() These results have led to various genetic approaches to the reactivation of HbF that are now being explored as therapeutic options in SCA ( 96). Genome-wide association studies of HbF, a quantitative trait that influences SCA severity, identified two quantitative trait loci that are not linked to the HBB cluster: BCL11A and HBS1-MYB ( 122, 195). ![]() ![]() More recently, SCA has demonstrated the potential for genome-wide association studies in the discovery of interacting genes that might be of clinical or therapeutic significance. The contribution of genetic modifiers to its extreme clinical heterogeneity made SCA an exemplar of the effects of genetic background on a single-gene disease. Because of this disease’s genetic simplicity, being caused by a single change in a single gene, it has been used to illustrate and validate many of the advances in this field, including proof-of-principle studies in DNA diagnostics, predictive genetics, and population and epidemiological genetics ( 104, 146, 167, 171). SCA, therefore, has always been at the forefront of molecular medicine and arguably launched the whole field of human molecular genetics. ( 83) showed that this amino acid substitution arose from a single base change (A>T) at codon 6 (rs334). In 1957, Ingram ( 100) discovered that HbS was caused by a single amino acid substitution (glutamic acid changed to valine) at position 6 of the β-globin chain of hemoglobin, and in 1963, Goldstein et al. ( 149) ascribed its basis to the presence of an abnormal hemoglobin, hemoglobin S (HbS), in 1949. SCA was subsequently heralded as the first “molecular disease” when Pauling et al. Sickle cell anemia (SCA) has been recognized in Africa for generations however, it was not formally described in the western literature until November 1910, when Herrick ( 93) reported a case of anemia that was associated with “peculiar elongated and sickle-shaped red blood corpuscles” on microscopy in a dental student from Grenada. Encouragingly, after a century of neglect, the profile of the vast majority of those with SCA in Africa and India is also finally improving. Meanwhile, an unprecedented number of new drugs aimed at both the treatment and prevention of end-organ damage are now in the pipeline, outcomes from potentially curative treatments such as allogeneic hematopoietic stem cell transplantation are improving, and great strides are being made in gene therapy, where methods employing both antisickling β-globin lentiviral vectors and gene editing are now entering clinical trials. A more detailed understanding of the switch from fetal to adult hemoglobin and the identification of regulators such as BCL11A provide hope that these findings will be translated into genomic-based approaches to the therapeutic reactivation of hemoglobin F production in patients with SCA. Recent years, however, have seen major advances on several fronts. By contrast, the translation of such knowledge into treatments that improve the lives of those affected has been much too slow. In the 100 years since sickle cell anemia (SCA) was first described in the medical literature, studies of its molecular and pathophysiological basis have been at the vanguard of scientific discovery. ![]()
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