Genome-wide Association Study Identifies Genetic Variants Influencing F-cell Levels in Sickle-Cell Patients

J Hum Genet. 2011 Apr;56(4):316-23. doi: 10.1038/jhg.2011.12. Epub 2011 Feb 17.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • African Continental Ancestry Group / 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
  • Glucagon-Like Peptide-1 Receptor
  • Haplotypes / genetics
  • Humans
  • Male
  • Nuclear Proteins / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Receptors, Glucagon / genetics
  • Repressor Proteins

Substances

  • BCL11A protein, human
  • Carrier Proteins
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Nuclear Proteins
  • Receptors, Glucagon
  • Repressor Proteins
  • Fetal Hemoglobin