Haematologica (Oct 2022)

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

  • Thomas Pincez,
  • Ken Sin Lo,
  • Anne-Laure Pham Hung d’Alexandry d’Orengiani,
  • Melanie E. Garrett,
  • Carlo Brugnara,
  • Allison E. Ashley-Koch,
  • Marilyn J. Telen,
  • Frederic Galacteros,
  • Philippe Joly,
  • Pablo Bartolucci,
  • Guillaume Lettre

DOI
https://doi.org/10.3324/haematol.2022.281180
Journal volume & issue
Vol. 108, no. 3

Abstract

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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.