The discovery of genetic loci associated with fetal hemoglobin levels in sickle cell disease patients through epigenomic prioritization. (Oral Presentation)


The clinical severity of sickle cell disease (SCD) and β-thalassemia, the major hemoglobinopathies which affect millions of patients worldwide, can be ameliorated by increased production of fetal hemoglobin (HbF). To date, genome-wide association studies have uncovered three main loci (BCL11A, HBS1L-Myb, and the HBB cluster) that modulate levels of HbF and together account for upwards of 50% of heritability in different populations. In this study, we sought not only to identify new loci by perfoming a step-wise conditional meta-analysis of HbF in ~3400 SCD patients of Africans ancestry and ~6000 healthy Sardinians, but also to understand the regulatory role of these genetic variations by integrating epigenomic annotations. We discovered an intronic common variant (rs4433524, P=3.8x10-8), which maps to BICC1, a gene that encodes for a protein shown in mouse model to have an impact on polycystic kidney disease. Furthermore, we discovered in the Sardinian cohort a non-synonymous variant (rs558942739) which introduces a premature stop codon in the erythroid transcription factor gene KLF1, and a missense variant (rs781260995, P=7.3x10-17) in FBXW9. It is unclear whether or not this KLF1 stop codon mutation is in linkage disequilibrium with the previously reported sentinel SNP (rs183437571) at NFIX. Finally, rs558942739 maps to DNAseI-hypersensitive sites specific to mature red blood cells.

Jan 1, 0001 12:00 AM — Jun 10, 2017 12:00 AM
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