Entire Expressed Peripheral Blood Transcriptome in Pediatric Severe Malarial Anemia

Anyona, Samuel B.; Cheng, Qing; Guo, Yan; Raballah, Evans; Hurwitz, Ivy; Onyango, Clinton; Seidenberg, Philip; Schneider, Kristan A.; Lambert, Christophe G; McMahon, Benjamin H.; Ouma, Collins; Perkins, Douglas J

doi:10.21203/rs.3.rs-3150748/v1

Cited by 3 publications

(2 citation statements)

References 79 publications

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“…The strongest effect was observed for the SMA sub-phenotype, however, this did not reach statistical significance. Interestingly, a recent report demonstrated an association between circulating neutrophil transcriptional activity and levels of anaemia in children with malaria [24], highlighting the need for further pathophysiological studies. We also observed little evidence for an effect of SM on neutrophil count.…”

Section: Discussionmentioning

confidence: 99%

“…Neutrophils have recently been shown to have a detrimental role in malaria, promoting pathogenesis by enhancing sequestration of iRBCs [4] and contributing to inflammatory tissue damage [6,22,23]. Altered neutrophil responses have also been linked to severe malarial anemia in paediatric patients [24]. On the other hand, neutrophils have also been suggested to participate in parasite clearance [25] and in shaping the Plasmodium antigenic repertoire [26].…”

Section: Introductionmentioning

confidence: 99%

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Investigating a causal role for neutrophil count onP. falciparumsevere malaria: a Mendelian Randomization study

Constantinescu,

Hughes,

Bull

et al. 2023

Preprint

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Background Malaria caused by P. falciparum imposes a tremendous public health burden on people living in sub-Saharan Africa. Severe malaria is associated with high morbidity and mortality and results from complications such as cerebral malaria, severe anaemia or respiratory distress. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to a heritable phenomenon called "benign ethnic neutropenia" (BEN). Neutrophils defend against bacterial infections but have been shown to be detrimental in pre-clinical malaria models, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. We tested this hypothesis by performing a genome-wide association study (GWAS) of circulating neutrophil count and a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria in individuals of predominantly African ancestry. Results We carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank (N=5,976). We identified previously unknown loci regulating neutrophil count in a non-European population. This was followed by a two-sample bi-directional MR analysis between neutrophil count and severe malaria (MalariaGEN, N=17,056). We identified 73 loci (r2=0.1) associated with neutrophil count, including the well-known rs2814778 variant responsible for BEN. The greatest evidence for an effect was found between neutrophil count and severe anaemia, although the confidence intervals crossed the null. MR analyses failed to suggest evidence for an effect of the combined severe malaria syndromes or individual subtypes (severe malaria anaemia, cerebral malaria, other severe malaria) on neutrophil count. Conclusion Our GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link between neutrophils and severe malarial anemia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Investigating a causal role for neutrophil count onP. falciparumsevere malaria: a Mendelian Randomization study

Constantinescu,

Hughes,

Bull

et al. 2023

Preprint

View full text Add to dashboard Cite

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The impact of Plasmodium-driven immunoregulatory networks on immunity to malaria

Boyle,

Engwerda,

Jagannathan

2024

Nat Rev Immunol

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A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis

Constantinescu,

Hughes,

Bull

et al. 2024

Hum Genomics

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Background 'Benign ethnic neutropenia' (BEN) is a heritable condition characterized by lower neutrophil counts, predominantly observed in individuals of African ancestry, and the genetic basis of BEN remains a subject of extensive research. In this study, we aimed to dissect the genetic architecture underlying neutrophil count variation through a linear-mixed model genome-wide association study (GWAS) in a population of African ancestry (N = 5976). Malaria caused by P. falciparum imposes a tremendous public health burden on people living in sub-Saharan Africa. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to BEN, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. As a follow-up, we tested this hypothesis by conducting a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria (MalariaGEN, N = 17,056). Results We carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank, identifying 73 loci (r2 = 0.1) and 10 index SNPs (GCTA-COJO loci) associated with neutrophil count, including previously unknown rare loci regulating neutrophil count in a non-European population. BOLT-LMM was reliable when conducted in a non-European population, and additional covariates added to the model did not largely alter the results of the top loci or index SNPs. The two-sample bi-directional MR analysis between neutrophil count and severe malaria showed the greatest evidence for an effect between neutrophil count and severe anaemia, although the confidence intervals crossed the null. Conclusion Our GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link between neutrophils and severe malaria.

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Entire Expressed Peripheral Blood Transcriptome in Pediatric Severe Malarial Anemia

Cited by 3 publications

References 79 publications

Investigating a causal role for neutrophil count onP. falciparumsevere malaria: a Mendelian Randomization study

Investigating a causal role for neutrophil count onP. falciparumsevere malaria: a Mendelian Randomization study

The impact of Plasmodium-driven immunoregulatory networks on immunity to malaria

A genome-wide association study of neutrophil count in individuals associated to an African continental ancestry group facilitates studies of malaria pathogenesis

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