Powars D R, Chan L, Schroeder W A
Department of Pediatrics, University of Southern California School of Medicine, Los Angeles 90033.
Ann N Y Acad Sci. 1989;565:262-78. doi: 10.1111/j.1749-6632.1989.tb24174.x.
The variable levels of HbF in sickle cell anemia reflect the heterogeneous genetic mix of the beta s-gene-cluster haplotypes and coinheritance of alpha-thalassemia-2 in American SS patients. Clinical severity is less when the level of HbF reaches 20% or 1.2 g/dl or more. The coinheritance of alpha-thalassemia-2 not only increases the intracellular red cell water but modifies the HbF level in accordance with the beta-cluster haplotype. In general, the SS patient with at least one Senegalese haplotype who does not have a CAR haplotype in trans, has a significantly greater probability of maintaining HbF above 20%. This is in part related to the genetic control of the G gamma HbF locus. Such a patient is protected from arteriolar vasculopathy and subsequent major organ destruction. Much of this but perhaps not all of the better health of patients with a Senegalese haplotype can be attributed to the elevation of G gamma HbF. The coinheritance of alpha-thalassemia-2 further decreases the risk of major morbidity of the soft tissues but increases the risk of avascular necrosis of the bony skeleton. Although these heterozygous Senegal patients are healthier, eventually most, in time, will show the deleterious effect of HbS as retinopathy and avascular necrosis usually beginning after age 30 and sickle nephropathy after age 40. Because of the age-specific effect, the onset of the sickle vasculopathy is delayed by nearly 20 years in the Sen/Ben patient with increased G gamma HbF as compared to those with a CAR haplotype or the homozygous Benin. Lifetime elevation of HbF above 20% modifies the severity of disease expression and provides relative protection to the patient with sickle cell anemia.
镰状细胞贫血患者中HbF水平的变化反映了美国SS患者βs基因簇单倍型的异质基因组合以及α地中海贫血-2的共遗传情况。当HbF水平达到20%或1.2 g/dl及以上时，临床严重程度较低。α地中海贫血-2的共遗传不仅增加了细胞内红细胞水分，还根据β基因簇单倍型改变了HbF水平。一般来说，至少有一个塞内加尔单倍型且不存在反式CAR单倍型的SS患者，维持HbF高于20%的可能性显著更高。这部分与GγHbF基因座的遗传控制有关。这类患者可免受小动脉血管病变及随后的主要器官破坏。塞内加尔单倍型患者的这种较好健康状况（但可能不是全部）很大程度上可归因于GγHbF的升高。α地中海贫血-2的共遗传进一步降低了软组织严重发病的风险，但增加了骨骼无血管坏死的风险。尽管这些杂合的塞内加尔患者更健康，但最终大多数人，随着时间推移，仍会表现出HbS的有害影响，如视网膜病变和无血管坏死通常在30岁后开始，镰状肾病在40岁后开始。由于年龄特异性影响，与具有CAR单倍型或纯合贝宁型的患者相比，GγHbF升高的Sen/Ben患者镰状血管病变的发病延迟了近20年。HbF终身高于20%可改变疾病表现的严重程度，并为镰状细胞贫血患者提供相对保护。
