Variation and heritability of Hb F and F-cells among beta-thalassemia heterozygotes in Hong Kong.
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.
Gibney
Geoffrey T
GT
Division of Hematology/Oncology, Department of Medicine, Boston University, Boston, Massachusetts02118., USA.
Panhuysen
Carolien I M
CI
So
Jason C C
JC
Ma
Edmond S K
ES
Ha
Shau Yin
SY
Li
Chi Kong
CK
Lee
Anselm C W
AC
Li
Chi Keung
CK
Yuen
Hui Leung
HL
Lau
Yu Lung
YL
Johnson
David M
DM
Farrell
John J
JJ
Bisbee
Alice B
AB
Farrer
Lindsay A
LA
Steinberg
Martin H
MH
Chan
Li Chong
LC
Chui
David H K
DH
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*
D005319:Fetal Hemoglobin; C028649:endodeoxyribonuclease XmnI; D015252:Deoxyribonucleases, Type II Site-Specific