1. A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression
- Author
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Shau Yin Ha, Rever Chak-ho Li, Hong-Yuan Luo, Hui Leung Yuen, Richard Sherva, Martin H. Steinberg, Paola Sebastiani, John J. Farrell, David H.K. Chui, Chi Keung Li, Zhi-yi Chen, Li Chong Chan, Lindsay A. Farrer, Acw Lee, Clinton T. Baldwin, Benjamin F. Chu, Chi Kong Li, Vivian Chan, Edmond S. K. Ma, and Jason C. C. So
- 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 - 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., link_to_subscribed_fulltext
- Published
- 2011