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Production of F cells in sickle cell anemia: regulation by a genetic locus
or loci separate from the beta-globin gene cluster
SH Boyer, GJ Dover, GR Serjeant, KD Smith, SE Antonarakis, SH Embury, L Margolet, AN Noyes, ML Boyer and WB Bias
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 beta- globin gene cluster, percentages
of F reticulocytes were compared in 59 sib pairs composed solely 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 beta
S. 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 for percent F reticulocytes fell within 99.9%
confidence limits or were alike by t test (P greater than or equal to .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 less than or equal to .005 and usually less than or equal to
10(-4). We next minimized the contribution of half-sibs among Jamaicans by
a combination of paternity testing and sib-sib comparison of beta-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 beta-globin
gene cluster. Still unanswered is (1) whether or not these genes are
actually linked to beta S, (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.
Volume 64,
Issue 5,
pp. 1053-1058,
11/01/1984
Copyright © 1984 by The American Society of Hematology
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