RESUMEN
Five factors have been shown to influence the 20-fold variation of fetal hemoglobin (Hb F) levels in sickle cell anemia (SS): age, sex, the O-globin gene number, á-globin haplotypes, and an X-linked locus that regulates the production of Hb F-containing erythrocytes (F cells), i.e., the F-cell production (FCP) locus. To determine the relative importance of these factors, we studied 257 Jamaican SS subjects from a cohort group identified by newborn screening and from a sib pair study. Linear regression analyses showed that each variable, when analyzed alone, had a significant association with Hb F levels (P < 0.05). Multiple regression analysis, including all variables, showed that the FCP locus is the strongest predictor, accounting for 40 percent of Hb F variation. á-Globin haplotypes, O-globin genes, and age accounted for less than 10 percent of the variation. The association between the á-globin haplotypes and Hb F levels becomes apparent if the influence of the FCP locus is removed by analyzing only individuals with the same FCP phenotype. Thus, the FCP locus is the most important factor identified to date in determining Hb F levels. The variation within each FCP phenotype is modulated by factors associated with the three common á-globin haplotypes and other as yet unidentified factor(s).(AU)
Asunto(s)
Humanos , Recién Nacido , Lactante , Preescolar , Niño , Adolescente , Adulto , Hemoglobina Fetal/genética , Anemia de Células Falciformes/genética , Variación Genética , Anemia de Células Falciformes/sangre , Estudios de CohortesRESUMEN
Levels of fetal hemoglobin (HbF) bearing reticulocytes (F reticulocytes) range from 2 percent to 50 percent 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 á- 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 ás. 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 percent confidence limits or were alike by t test (Po .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 ó .005 and usually ó 10 to the 4th power. We next minimized the contribution of half-sibs among Jamaicans by a combination of paternity testing and sib-sib comparison of á-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 á-globin gene cluster. Still unanswered is (1) whether or not these genes are actually linked to á to the s power, (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 (AU)