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Identification of genetic variants associated with clinical features of sickle cell disease

Affiliations
  • 1Division of Pulmonary and Sleep Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.
  • 2The Center for Applied Genomics, Children’s Hospital of Philadelphia, Research Institute, Leonard Madlyn Abramson Research Center, Suite 1216E, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.
  • 3Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.
  • 4Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
  • 5The Center for Applied Genomics, Children’s Hospital of Philadelphia, Research Institute, Leonard Madlyn Abramson Research Center, Suite 1216E, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA. hakonarson@chop.edu.
  • 6Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. hakonarson@chop.edu.

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August 29, 2024

Abstract

Sickle cell disease (SCD) is an inherited blood disorder marked by homozygosity of hemoglobin S, which is a defective hemoglobin caused by a missense mutation in the β-globin gene. However, clinical phenotypes of SCD vary among patients. To investigate genetic variants associated with various clinical phenotypes of SCD, we genotyped DNA samples from 520 SCD subjects and used a genome-wide association study (GWAS) approach to identify genetic variants associated with phenotypic features of SCD. For HbF levels, the previously reported 2p16.1 locus (BCL11A) reached genome significance (rs1427407, P = 8.58 × 10) in our GWAS as expected. In addition, we found a new genome-wide significance locus at 15q14 (rs8182015, P = 2.07 × 10) near gene EMC7. GWAS of acute chest syndrome (ACS) detected a locus (rs79915189, P = 3.70 × 10) near gene IDH2 at 15q26.1. The SNP, rs79915189, is also an expression quantitative trait locus (eQTL) of IDH2 in multiple tissues. For vasoocclusive episode (VOE), GWAS detected multiple significant signals at 2p25.1 (rs62118798, P = 4.27 × 10), 15q26.1 (rs62020555, P = 2.04 × 10) and 15q26.3 (rs117797325, P = 4.63 × 10). Our findings provide novel insights into the genetic mechanisms of SCD suggesting that common genetic variants play an important role in the presentation of the clinical phenotypes of patients with SCD.

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