期刊
JOURNAL OF HUMAN GENETICS
卷 56, 期 4, 页码 316-323出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/jhg.2011.12
关键词
BCL11A; F-cell regulation; fetal hemoglobin; GLP2R; GWAS; sickle-cell disease; SIT Trial cohort
资金
- National Heart, Lung and Blood Institute (NHLBI) [U54HL090515, 5R01HL091759]
- National Institute of Neurological Disorders and Stroke (NINDS) [NIH-NINDS 5U01-NS042804-03]
- National Institutes of Health [HHSN268200782096C]
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 x 10(-13)), but also identifies an independent novel intronic SNP, rs7606173, associated with F-cells (P-value < 1.81 x 10(-15)). The F-cell variances explained independently by these two SNPs are similar to 13% (rs7606173) and similar to 11% (rs766432), whereas, together they explain similar to 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 x 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. Journal of Human Genetics (2011) 56, 316-323; doi:10.1038/jhg.2011.12; published online 17 February 2011
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