Fetal hemoglobin levels in sickle cell disease and normal individuals are partially controlled by an X-linked gene located at Xp22.2

G. J. Dover, K. D. Smith, Y. C. Chang, S. Purvis, A. Mays, D. A. Meyers, C. Sheils, G. Serjeant

Research output: Contribution to journalArticle

Abstract

Fetal hemoglobin (Hb F) production in sickle cell (SS) disease and in normal individuals varies over a 20-fold range and is under genetic control. Previous studies suggested that variant Hb F levels might be controlled by genetic loci separate from the β-globin complex on chromosome 11. Using microscopic radial immunodiffusion and flow cytometric immunofluorescent assays to determine the percentage of F reticulocytes and F cells in SS and nonanemic individuals, we observed that F-cell levels were significantly higher in nonanemic females than males (mean ± SD, 3.8% ± 3.2% v 2.7% ± 2.3%). F-cell production as determined by F reticulocyte levels in SS females was also higher than in SS males (17% ± 10% v 13% ± 8%). We tested the hypothesis that F-cell production in both normal and anemic SS individuals was controlled by an X-linked locus with two alleles, high (H) and low (L). Using an algorithm to determine the 99.8% confidence interval of a normal distribution in nonanemic individuals, we estimated that males and females with at least one H allele had greater than 3.3% F cells. Comparisons of male-male or female-female SS sib pairs with discordant F reticulocyte levels distinguished two phenotypes in SS males (L, <12%; H, >12%) and three phenotypes in SS females (LL, <12%; HL, 12% to 24%, HH >24%). Linkage analysis using polymorphic restriction sites along the X chromosome in eight SS and one AA family localized the F-cell production (FCP) locus to Xp22.2, with a maximum lod score (logarithm of odds of linkage v independent assortment) of 4.6 at a recombination fraction of 0.04.

Original languageEnglish (US)
Pages (from-to)816-824
Number of pages9
JournalBlood
Volume80
Issue number3
StatePublished - Jan 1 1992

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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