Abstract
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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Acknowledgements
We thank the staff, clinicians and patients for their participation in the Silent Infarct Transfusion (SIT) Trial study. This study was supported by the National Heart, Lung and Blood Institute (NHLBI) (award number: U54HL090515, 5R01HL091759) and the National Institute of Neurological Disorders and Stroke (NINDS) (NIH-NINDS 5U01-NS042804-03). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University (CIDR contract number: HHSN268200782096C).
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Bhatnagar, P., Purvis, S., Barron-Casella, E. et al. Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients. J Hum Genet 56, 316–323 (2011). https://doi.org/10.1038/jhg.2011.12
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