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

• Published in: Haematologica (Roma) 2023-03, Vol.108 (3), p.870-881
• Main Authors: Pincez, Thomas, Lo, Ken Sin, D'Orengiani, Anne-Laure Pham Hung d'Alexandry, Garrett, Melanie E, Brugnara, Carlo, Ashley-Koch, Allison E, Telen, Marilyn J, Galacteros, Frederic, Joly, Philippe, Bartolucci, Pablo, Lettre, Guillaume
• Format: Article
• Language: English
• Subjects: Anemia, Sickle Cell - complications; Anemia, Sickle Cell - genetics; Fetal Hemoglobin - genetics; Genome-Wide Association Study; Genotype; Humans; Multifactorial Inheritance; Red Cell Biology & its Disorders; Stroke
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2022.281180

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.