Splenic clearance of rigid erythrocytes as an inherited mechanism for splenomegaly and natural resistance to malaria.
Anemia
/ genetics
Cohort Studies
DNA-Binding Proteins
/ genetics
Erythrocytes
/ parasitology
Genome-Wide Association Study
Humans
Immunity, Innate
Immunoglobulin M
Malaria
Malaria, Falciparum
/ parasitology
Membrane Proteins
/ genetics
Phosphoric Diester Hydrolases
Plasmodium falciparum
/ genetics
RNA-Binding Proteins
/ genetics
Spleen
Splenomegaly
/ genetics
Erythrocytes
Ethnic groups
Falciparum
Genome-wide association study
Heritability
Malaria
Spleen
Splenomegaly
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Aug 2022
Aug 2022
Historique:
received:
21
03
2022
revised:
25
05
2022
accepted:
30
06
2022
pubmed:
18
7
2022
medline:
17
8
2022
entrez:
17
7
2022
Statut:
ppublish
Résumé
In malaria-endemic areas, subjects from specific groups like Fulani have a peculiar protection against malaria, with high levels of IgM but also frequent anaemia and splenomegaly. The mechanisms underlying this phenotype remain elusive. In a cohort study set up in Benin, West Africa, after a careful evaluation of malaria-related phenotypes, we measured the deformability of circulating erythrocytes in genetically distinct groups (including Fulani) living in sympatry, using ektacytometry and microsphiltration, a mimic of how the spleen clears rigid erythrocytes. Heritability of erythrocytes deformability was calculated, followed by a genome-wide association study (GWAS) of the same phenotype. Compared to non-Fulani, Fulani displayed a higher deformability of circulating erythrocytes, pointing to an enhanced clearance of rigid erythrocytes by the spleen. This phenotype was observed in individuals displaying markers of Plasmodium falciparum infection. The heritability of this new trait was high, with a strong multigenic component. Five of the top 10 genes selected by a population structure-adjusted GWAS, expressed in the spleen, are potentially involved in splenic clearance of erythrocytes (CHERP, MB, PALLD, SPARC, PDE10A), through control of vascular tone, collagen synthesis and macrophage activity. In specific ethnic groups, genetically-controlled processes likely enhance the innate retention of infected and uninfected erythrocytes in the spleen, explaining splenomegaly, anaemia, cryptic intrasplenic parasite loads, hyper-IgM, and partial protection against malaria. Beyond malaria-related phenotypes, inherited splenic hyper-filtration of erythrocytes may impact the pathogenesis of other hematologic diseases. ANR, National Geographic Society, IMEA, IRD, and Région Ile-de-France.
Sections du résumé
BACKGROUND
BACKGROUND
In malaria-endemic areas, subjects from specific groups like Fulani have a peculiar protection against malaria, with high levels of IgM but also frequent anaemia and splenomegaly. The mechanisms underlying this phenotype remain elusive.
METHODS
METHODS
In a cohort study set up in Benin, West Africa, after a careful evaluation of malaria-related phenotypes, we measured the deformability of circulating erythrocytes in genetically distinct groups (including Fulani) living in sympatry, using ektacytometry and microsphiltration, a mimic of how the spleen clears rigid erythrocytes. Heritability of erythrocytes deformability was calculated, followed by a genome-wide association study (GWAS) of the same phenotype.
FINDINGS
RESULTS
Compared to non-Fulani, Fulani displayed a higher deformability of circulating erythrocytes, pointing to an enhanced clearance of rigid erythrocytes by the spleen. This phenotype was observed in individuals displaying markers of Plasmodium falciparum infection. The heritability of this new trait was high, with a strong multigenic component. Five of the top 10 genes selected by a population structure-adjusted GWAS, expressed in the spleen, are potentially involved in splenic clearance of erythrocytes (CHERP, MB, PALLD, SPARC, PDE10A), through control of vascular tone, collagen synthesis and macrophage activity.
INTERPRETATION
CONCLUSIONS
In specific ethnic groups, genetically-controlled processes likely enhance the innate retention of infected and uninfected erythrocytes in the spleen, explaining splenomegaly, anaemia, cryptic intrasplenic parasite loads, hyper-IgM, and partial protection against malaria. Beyond malaria-related phenotypes, inherited splenic hyper-filtration of erythrocytes may impact the pathogenesis of other hematologic diseases.
FUNDING
BACKGROUND
ANR, National Geographic Society, IMEA, IRD, and Région Ile-de-France.
Identifiants
pubmed: 35843175
pii: S2352-3964(22)00348-6
doi: 10.1016/j.ebiom.2022.104167
pmc: PMC9297103
pii:
doi:
Substances chimiques
CHERP protein, human
0
DNA-Binding Proteins
0
Immunoglobulin M
0
Membrane Proteins
0
RNA-Binding Proteins
0
PDE10A protein, human
EC 3.1.4.-
Phosphoric Diester Hydrolases
EC 3.1.4.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104167Informations de copyright
Copyright © 2022. Published by Elsevier B.V.
Déclaration de conflit d'intérêts
Declaration of interests Dr Clain reports receiving a grant from the French national research agency (Grant ANR-17-CE15-0013-03) to conduct research (materials, equipment, post-doc salary) on artemisinin resistance in malaria parasites. All the other authors have declared no conflict of interest.