Production of F Cells in Sickle Cell Anemia: Regulation by a Genetic Locus or Loci Separate From the β-Globin Gene Cluster

• Published in: Blood 1984-11, Vol.64 (5), p.1053-1058
• Main Authors: Boyer, Samuel H., Dover, George J., Serjeant, Graham R., Smith, Kirby D., Antonarakis, Stylianos E., Embury, Stephen H., Margolet, Louise, Noyes, Andrea N., Boyer, Marian L., Bias, Wilma B.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Alleles; Anemia, Sickle Cell - blood; Anemia, Sickle Cell - genetics; Anemias. Hemoglobinopathies; Biological and medical sciences; Child; Diseases of red blood cells; Family; Fetal Hemoglobin - analysis; Gene Expression Regulation; Hematologic and hematopoietic diseases; Humans; Medical sciences; Reticulocytes - analysis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V64.5.1053.1053

Levels of fetal hemoglobin (HbF) bearing reticulocytes (F reticulocytes) range from 2% to 50% in patients with sickle cell (SS) anemia. To learn whether any portion of such variation in F cell production is regulated by loci genetically separable from the β-globin gene cluster, percentages of F reticulocytes were compared in 59 sib pairs composed soley of SS members, including 40 pairs from Jamaica and 19 from the United States. We reasoned that differences in F reticulocyte levels might arise (1) from any of several kinds of artifact, (2) via half-sib status, or (3) because one or more genes regulating F cell production segregate separately from βS. We minimized the role of artifact by assay of fresh samples from 84 SS individuals, including both members of 38 sib pairs. In 78 of the 84 subjects, serial values sfor percent F reticulocytes fell within 99.9% confidence limits or were alike by t test (P ≥ .05). This left 32 sib pairs for which F reticulocyte levels in each member were reproducible. When sib–sib comparisons were limited to these 32 pairs, percentages of F reticulocytes were grossly dissimilar within 12 Jamaican and 3 American sibships. Within them, the probability that sibs were alike was always ≤ .005 and usually ≤ 10–4. We next minimized the contribution of half-sibs among Jamaicans by a combination of paternity testing and sib–sib comparison of β-globin region DNA restriction fragment length polymorphisms, especially among discordant pairs. We thereafter concluded that at least seven to eight Jamaican pairs were composed of reproducibly discordant full sibs. There is thus little doubt that there are genes regulating between-patient differences in F cell production that are separate from the β-globin gene cluster. Still unanswered is (1) whether or not these genes are actually linked to βS, (2) why F reticulocyte levels in Americans tend to be lower than in Jamaicans, and (3) whether or not differences in F cell production among SS patients are regulated by several major loci or by only one.