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A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression
- Publication Year :
- 2011
- Publisher :
- American Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org, 2011.
-
Abstract
- Fetal hemoglobin (HbF) is regulated as a multigenic trait. By genome-wide association study, we confirmed that HBS1L-MYB intergenic polymorphisms (HMIP) and BCL11A polymorphisms are highly associated with HbF in Chinese β-thalassemia heterozygotes. In this population, the variance in HbF resulting from the HMIP is 13.5%; that resulting from the BCL11A polymorphism is 6.4%. To identify the functional variant in HMIP, we used 1000 Genomes Project data, single nucleotide polymorphism imputation, comparisons of association results across populations, potential transcription factor binding sites, and analysis of phylogenetic conservation. Based on these studies, a hitherto unreported association between HbF expression and a 3-bp deletion, between 135 460 326 and 135 460 328 bp on chromosome 6q23 was found. This 3-bp deletion is in complete linkage disequilibrium with rs9399137, which is the single nucleotide polymorphism in HMIP most significantly associated with HbF among Chinese, Europeans, and Africans. Chromatin immunoprecipitation assays confirmed erythropoiesis-related transcription factors binding to this region in K562 cells. Based on transient expression of a luciferase reporter plasmid, the DNA fragment encompassing the 3-bp deletion polymorphism has enhancer-like activity that is further augmented by the introduction of the 3-bp deletion. This 3-bp deletion polymorphism is probably the most significant functional motif accounting for HMIP modulation of HbF in all 3 populations. © 2011 by The American Society of Hematology.<br />link_to_subscribed_fulltext
- Subjects :
- Adult
Male
Heterozygote
Linkage disequilibrium
Genes, myb
DNA Mutational Analysis
Molecular Sequence Data
Quantitative Trait Loci
Immunology
Population
Gene Expression
Single-nucleotide polymorphism
Genome-wide association study
Biology
Polymorphism, Single Nucleotide
Biochemistry
HBG2
Linkage Disequilibrium
Cohort Studies
Red Cells, Iron, and Erythropoiesis
Asian People
hemic and lymphatic diseases
Humans
education
Gene
Fetal Hemoglobin
DNA Primers
Sequence Deletion
Genetics
education.field_of_study
Base Sequence
beta-Thalassemia
Chromosome
Cell Biology
Hematology
Molecular biology
Fetal Hemoglobin - genetics
DNA binding site
Enhancer Elements, Genetic
Asian Continental Ancestry Group - genetics
Hong Kong
Chromosomes, Human, Pair 6
DNA, Intergenic
Female
K562 Cells
Chromosomes, Human, Pair 6 - genetics
Genome-Wide Association Study
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....747aa9966dc8b2619bb3ea9b5232dafd