Beta s-gene-cluster haplotypes in sickle cell anemia. Clinical and hematologic features.

Identification of the beta s-gene-cluster haplotype and alpha-gene status provides a useful tool for the detection of the high-risk SS patient. The DNA polymorphisms of the beta s-gene-cluster modulate the clinical course in sickle cell anemia, especially as it involves the risk of end stage organ failure of the kidney, lung, brain, eyes, bones, and leg ulcers. This is schematically represented in Figure 4. The disease severity is modified according to the beta s-gene-cluster haplotypes and the co-inheritance of alpha-thalassemia-2. In both Africa and America, the CAR beta s haplotype increases the risk of developing an irreversible complication at an early age. The rate of progression of organ damage is regulated by the beta s-cluster haplotype from birth. The preservation of G gamma Hb F is haplotype dependent and correlates with the overall clinical course of the patient. Further modulation of the clinical course with the co-inheritance of alpha-thalassemia-2 tends to decrease the risk of soft-tissue organ failure and increase the risk of osteonecrosis. Epidemiologic studies in Africa together with clinical correlative analysis in Southern California show that SS patients with a Ben haplotype have a less severe illness than those with a CAR and a more severe illness than those with a Sen. A single individual can be expected to fit into the overall pattern. Some sickle related illness will eventually occur in all. The variable clinical manifestations in sickle cell anemia are modified according to the interaction of alpha gene deletions and the beta s-gene-cluster haplotype, are distinct for each organ, and markedly influence the age of onset of end stage major organ failure. In the presence of a Senegal haplotype, the patient's health is better; with the CAR haplotype, it is always worse; severity is intermediate in the Benin haplotype.