title: Variation and heritability of Hb F and F-cells among beta-thalassemia heterozygotes in Hong Kong.
abstract: Enhanced fetal hemoglobin (Hb F) production can partially compensate for the lack of adult hemoglobin (Hb A) in patients with beta-thalassemia major or intermedia, and ameliorate the clinical severity of these diseases. To further elucidate factors governing Hb F levels, we evaluated demographic, clinical, laboratory, and genetic characteristics in 241 unrelated adult beta-thalassemia carriers in Hong Kong. They had wide variations in Hb F and F-cell numbers skewing toward higher levels. Individuals who coinherited the Xmn IT-allele in the (G)gamma-globin gene promoter had higher Hb F and more F-cells compared with those lacking the Xmn I T-allele. However, both groups exhibited a similarly wide spread of Hb F and F-cells. The correlation of Hb F and F-cells corresponded well to both linear and exponential models, suggesting multiple mechanisms for Hb F augmentation. The heritabilities of Hb F and F-cells were calculated in 66 families (111 parents who were beta-thalassemia carriers and 82 asymptomatic offspring) to be 0.7 to 0.9. The Xmn I polymorphism accounted for 9% of the Hb F and 13% of the F-cell heritabilities. These results suggest that these family members are well suited for genome wide association studies that will identify genetic loci regulating Hb F production, and likely novel pharmacological targets for reactivating Hb F production in adults.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Boston University, Boston, Massachusetts02118., USA.
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Gibney
authors.forename: Carolien I M
authors.initials: CI
authors.lastname: Panhuysen
authors.forename: Jason C C
authors.initials: JC
authors.lastname: So
authors.forename: Edmond S K
authors.initials: ES
authors.lastname: Ma
authors.forename: Shau Yin
authors.initials: SY
authors.lastname: Ha
authors.forename: Chi Kong
authors.initials: CK
authors.lastname: Li
authors.forename: Anselm C W
authors.initials: AC
authors.lastname: Lee
authors.forename: Chi Keung
authors.initials: CK
authors.lastname: Li
authors.forename: Hui Leung
authors.initials: HL
authors.lastname: Yuen
authors.forename: Yu Lung
authors.initials: YL
authors.lastname: Lau
authors.forename: David M
authors.initials: DM
authors.lastname: Johnson
authors.forename: John J
authors.initials: JJ
authors.lastname: Farrell
authors.forename: Alice B
authors.initials: AB
authors.lastname: Bisbee
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Martin H
authors.initials: MH
authors.lastname: Steinberg
authors.forename: Li Chong
authors.initials: LC
authors.lastname: Chan
authors.forename: David H K
authors.initials: DH
authors.lastname: Chui
mesh_terms: D015252:Deoxyribonucleases, Type II Site-Specific; D005192:Family Health; D005319:Fetal Hemoglobin / Q000032:analysis*; D006579:Heterozygote; D006723:Hong Kong / Q000453:epidemiology; D006801:Humans; D040582:Inheritance Patterns; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D017086:beta-Thalassemia / Q000097:blood / Q000453:epidemiology / Q000235:genetics*
chemical_list: D005319:Fetal Hemoglobin; C028649:endodeoxyribonuclease XmnI; D015252:Deoxyribonucleases, Type II Site-Specific