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Updated: Jun 14, 2025

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

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

Katharine Tsukahara1, Xiao Chang2, Frank Mentch2

  • 1Division of Pulmonary and Sleep Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Scientific Reports
|August 29, 2024
PubMed

Insights

This study identifies new genetic variants influencing sickle cell disease (SCD) severity and complications. These findings enhance our understanding of SCD

Area of Science:

  • Genetics
  • Hematology
  • Genomics

Background:

  • Sickle cell disease (SCD) is an inherited blood disorder caused by a mutation in the β-globin gene, leading to defective hemoglobin S.
  • Clinical manifestations of SCD exhibit significant variability among affected individuals.
  • Understanding the genetic underpinnings of SCD phenotypes is crucial for personalized medicine approaches.

Purpose of the Study:

  • To identify genetic variants associated with diverse clinical phenotypes in patients with sickle cell disease.
  • To explore the role of common genetic variants in the presentation of SCD.

Main Methods:

  • Genotyped DNA samples from 520 SCD subjects.
  • Employed a genome-wide association study (GWAS) approach to analyze genetic associations with SCD phenotypes.
  • Investigated associations with fetal hemoglobin (HbF) levels, acute chest syndrome (ACS), and vaso-occlusive episodes (VOE).

Main Results:

  • Confirmed the known 2p16.1 locus (BCL11A) associated with HbF levels.
  • Discovered a novel genome-wide significant locus at 15q14 (rs8182015) near the EMC7 gene for HbF levels.
  • Identified a locus near IDH2 at 15q26.1 (rs79915189) associated with ACS, which is also an eQTL for IDH2.
  • Detected multiple significant signals for VOE at 2p25.1, 15q26.1, and 15q26.3.

Conclusions:

  • Common genetic variants significantly contribute to the clinical variability observed in sickle cell disease.
  • Novel genetic loci associated with HbF levels and ACS provide new insights into SCD pathophysiology.
  • These findings pave the way for a deeper understanding of genetic mechanisms driving SCD phenotypes.

Keywords:
Fetal hemoglobinGenome-wide association studyHemoglobinopathiesSickle cell anemia

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