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
Affiliations
Thomas Pincez
Montreal Heart Institute, Montreal, Quebec, Canada; Department of Pediatrics, Division of Pediatric Hematology-Oncology, Charles-Bruneau Cancer Center, CHU Sainte-Justine, Universite de Montreal, Montreal, Quebec
Ken Sin Lo
Montreal Heart Institute, Montreal, Quebec
Anne-Laure Pham Hung d’Alexandry d’Orengiani
Red Cell Genetic Disease Unit, Hopital Henri-Mondor, Assistance Publique-Hopitaux de Paris (AP-HP), Universite Paris Est, IMRB - U955 - Equipe no 2, Creteil
Melanie E. Garrett
Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC
Carlo Brugnara
Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA
Allison E. Ashley-Koch
Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC
Marilyn J. Telen
Department of Medicine, Division of Hematology, Duke University Medical Center, Durham, NC
Frederic Galacteros
Red Cell Genetic Disease Unit, Hopital Henri-Mondor, Assistance Publique-Hopitaux de Paris (AP-HP), Universite Paris Est, IMRB - U955 - Equipe no 2, Creteil
Philippe Joly
Unite Fonctionnelle 34445 ‘Biochimie des Pathologies Erythrocytaires’, Laboratoire de Biochimie et Biologie Moleculaire Grand-Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France; Laboratoire Inter-Universitaire de Biologie de la Motricite (LIBM) EA7424, Equipe ‘Biologie Vasculaire et du Globule Rouge’, Universite Claude Bernard Lyon 1, Comite d’Universites et d’Etablissements (COMUE), Lyon
Pablo Bartolucci
Red Cell Genetic Disease Unit, Hopital Henri-Mondor, Assistance Publique-Hopitaux de Paris (AP-HP), Universite Paris Est, IMRB - U955 - Equipe no 2, Creteil
Guillaume Lettre
Montreal Heart Institute, Montreal, Quebec, Canada; Department of Medicine, Faculty of Medicine, Universite de Montreal, Montreal, Quebec
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.
