| Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients. | |
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MedLine Citation:
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PMID: 21326311 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Fetal hemoglobin (HbF) level has emerged as an important prognostic factor in sickle-cell disease (SCD) and can be measured by the proportion of HbF-containing erythrocytes (F-cells). Recently, BCL11A (zinc-finger protein) was identified as a regulator of HbF, and the strongest association signals were observed either directly for rs766432 or for correlated single-nucleotide polymorphisms (SNPs). To identify additional independently associated genetic variants, we performed a genome-wide association study (GWAS) on the proportion of F-cells in individuals of African ancestry with SCD from the Silent Infarct Transfusion (SIT) Trial cohort. Our study not only confirms the association of rs766432 (P-value <3.32 × 10(-13)), but also identifies an independent novel intronic SNP, rs7606173, associated with F-cells (P-value <1.81 × 10(-15)). The F-cell variances explained independently by these two SNPs are ∼13% (rs7606173) and ∼11% (rs766432), whereas, together they explain ∼16%. Additionally, in men, we identify a novel locus on chromosome 17, glucagon-like peptide-2 receptor (GLP2R), associated with F-cell regulation (rs12103880; P-value <3.41 × 10(-8)). GLP2R encodes a G protein-coupled receptor and involved in proliferative and anti-apoptotic cellular responses. These findings highlight the importance of denser genetic screens and suggest further exploration of the BCL11A and GLP2R loci to gain additional insight into HbF/F-cell regulation. |
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Authors:
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Pallav Bhatnagar; Shirley Purvis; Emily Barron-Casella; Michael R DeBaun; James F Casella; Dan E Arking; Jeffrey R Keefer |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-02-17 |
Journal Detail:
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Title: Journal of human genetics Volume: 56 ISSN: 1435-232X ISO Abbreviation: J. Hum. Genet. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-26 Completed Date: 2011-08-22 Revised Date: 2013-03-19 |
Medline Journal Info:
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Nlm Unique ID: 9808008 Medline TA: J Hum Genet Country: Japan |
Other Details:
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Languages: eng Pagination: 316-23 Citation Subset: IM |
Affiliation:
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McKusick-Nathans Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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African Continental Ancestry Group
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genetics* Anemia, Sickle Cell / genetics* Bayes Theorem Carrier Proteins / genetics* Chromosomes, Human, Pair 17 / genetics* Cohort Studies Erythrocyte Count Erythrocytes / metabolism* Fetal Hemoglobin / analysis* Genome-Wide Association Study Genotype Haplotypes / genetics Humans Male Nuclear Proteins / genetics* Polymorphism, Single Nucleotide / genetics Receptors, Glucagon / genetics |
| Grant Support | |
ID/Acronym/Agency:
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5R01HL091759/HL/NHLBI NIH HHS; 5U01-NS042804-03/NS/NINDS NIH HHS; HHSN268200782096C//PHS HHS; U54HL090515/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/BCL11A protein, human; 0/Carrier Proteins; 0/Nuclear Proteins; 0/Receptors, Glucagon; 0/glucagon-like peptide-1 receptor; 9034-63-3/Fetal Hemoglobin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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