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Variation and impact of polygenic hematologic traits in monogenic sickle cell disease.

Publication ,  Journal Article
Pincez, T; Lo, KS; D'Orengiani, A-LPHD; Garrett, ME; Brugnara, C; Ashley-Koch, AE; Telen, MJ; Galacteros, F; Joly, P; Bartolucci, P; Lettre, G
Published in: Haematologica
March 1, 2023

Several of the complications observed in sickle cell disease (SCD) are influenced by variation in hematologic traits (HT), such as fetal hemoglobin (HbF) level and neutrophil count. Previous large-scale genome-wide association studies carried out in largely healthy individuals have identified thousands of variants associated with HT, which have then been used to develop multi-ancestry polygenic trait scores (PTS). Here, we tested whether these PTS associate with HT in SCD patients and if they can improve statistical models associated with SCD-related complications. In 2,056 SCD patients, we found that the PTS predicted less HT variance than in non-SCD individuals of African ancestry. This was particularly striking at the Duffy/DARC locus, where we observed an epistatic interaction between the SCD genotype and the Duffy null variant (rs2814778) that led to a two-fold weaker effect on neutrophil count. PTS for these HT which are measured as part of routine practice were not associated with complications in SCD. In contrast, we found that a simple PTS for HbF that includes only six variants explained a large fraction of the phenotypic variation (20.5-27.1%), associated with acute chest syndrome and stroke risk, and improved the statistical modeling of the vaso-occlusive crisis rate. Using Mendelian randomization, we found that increasing HbF by 4.8% reduces stroke risk by 39% (P=0.0006). Taken together, our results highlight the importance of validating PTS in large diseased populations before proposing their implementation in the context of precision medicine initiatives.

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Published In

Haematologica

DOI

EISSN

1592-8721

Publication Date

March 1, 2023

Volume

108

Issue

3

Start / End Page

870 / 881

Location

Italy

Related Subject Headings

  • Stroke
  • Multifactorial Inheritance
  • Immunology
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Fetal Hemoglobin
  • Anemia, Sickle Cell
  • 3201 Cardiovascular medicine and haematology
  • 1102 Cardiorespiratory Medicine and Haematology
 

Citation

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Pincez, T., Lo, K. S., D’Orengiani, A.-L., Garrett, M. E., Brugnara, C., Ashley-Koch, A. E., … Lettre, G. (2023). Variation and impact of polygenic hematologic traits in monogenic sickle cell disease. Haematologica, 108(3), 870–881. https://doi.org/10.3324/haematol.2022.281180
Pincez, Thomas, Ken Sin Lo, Anne-Laure Pham Hung d’Alexandry D’Orengiani, Melanie E. Garrett, Carlo Brugnara, Allison E. Ashley-Koch, Marilyn J. Telen, et al. “Variation and impact of polygenic hematologic traits in monogenic sickle cell disease.Haematologica 108, no. 3 (March 1, 2023): 870–81. https://doi.org/10.3324/haematol.2022.281180.
Pincez T, Lo KS, D’Orengiani A-LPHD, Garrett ME, Brugnara C, Ashley-Koch AE, et al. Variation and impact of polygenic hematologic traits in monogenic sickle cell disease. Haematologica. 2023 Mar 1;108(3):870–81.
Pincez, Thomas, et al. “Variation and impact of polygenic hematologic traits in monogenic sickle cell disease.Haematologica, vol. 108, no. 3, Mar. 2023, pp. 870–81. Pubmed, doi:10.3324/haematol.2022.281180.
Pincez T, Lo KS, D’Orengiani A-LPHD, Garrett ME, Brugnara C, Ashley-Koch AE, Telen MJ, Galacteros F, Joly P, Bartolucci P, Lettre G. Variation and impact of polygenic hematologic traits in monogenic sickle cell disease. Haematologica. 2023 Mar 1;108(3):870–881.

Published In

Haematologica

DOI

EISSN

1592-8721

Publication Date

March 1, 2023

Volume

108

Issue

3

Start / End Page

870 / 881

Location

Italy

Related Subject Headings

  • Stroke
  • Multifactorial Inheritance
  • Immunology
  • Humans
  • Genotype
  • Genome-Wide Association Study
  • Fetal Hemoglobin
  • Anemia, Sickle Cell
  • 3201 Cardiovascular medicine and haematology
  • 1102 Cardiorespiratory Medicine and Haematology