Human genetic variant E756del in the ion channel <i>PIEZO1</i> not associated with protection from severe malaria in a large Ghanaian study

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Abstract

Recently, a common genetic variant E756del in the human gene PIEZO1 was associated with protection from severe malaria. Here, we performed a genetic association study of this gain-of-function variant in a large case-control study including 4149 children from the Ashanti Region in Ghana, West Africa. The statistical analysis did not indicate an association with protection from severe malaria and, thus, providing evidence against a strong protective effect of the PIEZO1 E756del variant on severe malaria susceptibility.

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Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection

Rakhee Lohia, Laurence Berry, Shahid Khan … (2018)

Hereditary xerocytosis is thought to be a rare genetic condition characterized by red blood cell (RBC) dehydration with mild hemolysis. RBC dehydration is linked to reduced Plasmodium infection in vitro ; however, the role of RBC dehydration in protection against malaria in vivo is unknown. Most cases of hereditary xerocytosis are associated with gain-of-function mutations in PIEZO1, a mechanically activated ion channel. We engineered a mouse model of hereditary xerocytosis and show that Plasmodium infection fails to cause experimental cerebral malaria in these mice due to the action of Piezo1 in RBCs and in T cells. Remarkably, we identified a novel human gain-of-function PIEZO1 allele, E756del, present in a third of African population. RBCs from individuals carrying this allele are dehydrated and display reduced Plasmodium infection in vitro . The existence of a gain-of-function PIEZO1 at such high frequencies is surprising, and suggests an association with malaria resistance. A gain of function mutation in the mechanically activated channel PIEZO1 is associated with resistance to the malaria parasite Plasmodium falciparum

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Insights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania

Gavin Band, Quang Si Le, Geraldine M Clarke … (2019)

The human genetic factors that affect resistance to infectious disease are poorly understood. Here we report a genome-wide association study in 17,000 severe malaria cases and population controls from 11 countries, informed by sequencing of family trios and by direct typing of candidate loci in an additional 15,000 samples. We identify five replicable associations with genome-wide levels of evidence including a newly implicated variant on chromosome 6. Jointly, these variants account for around one-tenth of the heritability of severe malaria, which we estimate as ~23% using genome-wide genotypes. We interrogate available functional data and discover an erythroid-specific transcription start site underlying the known association in ATP2B4, but are unable to identify a likely causal mechanism at the chromosome 6 locus. Previously reported HLA associations do not replicate in these samples. This large dataset will provide a foundation for further research on the genetic determinants of malaria resistance in diverse populations.

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Hemoglobin variants and disease manifestations in severe falciparum malaria.

Christa Ehmen, Patrick J C May, Thorsten Thye … (2007)

The geographical distributions of hemoglobin S (HbS), hemoglobin C (HbC), and alpha+-thalassemia (-alpha) strongly suggest balancing selection with malaria. However, whereas several studies indicate that the HbS carrier state protects against all major forms of clinical malaria, malaria protection on clinical grounds has been more difficult to confirm for HbC and -alpha, and questions remain as to whether it applies to all forms of the disease. To assess the association between major clinical forms of severe falciparum malaria and HbS, HbC, and -alpha. Case-control study of 2591 children with severe falciparum malaria enrolled at a tertiary referral center in Ghana, West Africa, and 2048 age-, sex-, and ethnicity-matched control participants recruited by community surveys. Frequencies of HbS, HbC, and -alpha in patients and controls, including stratifications of patients for signs of disease. Patients presented with partly overlapping signs of disease, including severe anemia (64%), cerebral malaria (22%), respiratory distress (30%), hyperparasitemia (32%), prostration (52%), acidosis (59%), and hyperlactatemia (56%). Carrier states of HbS, HbC, and -alpha were found in 1.4%, 9.4%, and 25.2% of the patients, respectively, and 14.8%, 8.7%, and 27.3% of controls. The HbS carrier state was negatively associated with all forms of the disease studied (overall odds ratio [OR], 0.08; 95% confidence interval [CI], 0.06-0.12). The HbC carrier state showed a negative association selectively with cerebral malaria (OR, 0.64; 95% CI, 0.45-0.91), and the -alpha carrier state showed a negative association selectively with severe anemia (OR, 0.82; 95% CI, 0.69-0.96). Whereas the HbS carrier state was found to be negatively associated with all major forms of severe falciparum malaria, the negative associations of the carrier states of HbC and -alpha appeared to be limited to cerebral malaria and severe anemia, respectively.

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Author and article information

Contributors

Thorsten Thye: thye@bnitm.de

Journal

Journal ID (nlm-ta): J Hum Genet

Journal ID (iso-abbrev): J Hum Genet

Title: Journal of Human Genetics

Publisher: Springer Singapore (Singapore )

ISSN (Print): 1434-5161

ISSN (Electronic): 1435-232X

Publication date (Electronic): 7 July 2021

Publication date PMC-release: 7 July 2021

Publication date (Print): 2022

Volume: 67

Issue: 1

Pages: 65-67

Affiliations

[1 ]GRID grid.424065.1, ISNI 0000 0001 0701 3136, Department of Infectious Disease Epidemiology, , Bernhard Nocht Institute for Tropical Medicine, ; Hamburg, Germany

[2 ]GRID grid.424065.1, ISNI 0000 0001 0701 3136, Department of Molecular Medicine, , Bernhard Nocht Institute for Tropical Medicine, ; Hamburg, Germany

[3 ]GRID grid.487281.0, Kumasi Centre for Collaborative Research in Tropical Medicine, ; Kumasi, Ghana

[4 ]GRID grid.415450.1, ISNI 0000 0004 0466 0719, University of Science and Technology, School of Medical Sciences, Kumasi, Ghana, Departments of Child Health and Medicine, Komfo Anokye Teaching Hospital, ; Kumasi, Ghana

[5 ]GRID grid.452463.2, German Center for Infection Research (DZIF), ; Hamburg-Lübeck-Borstel-Riems, Germany

Article

Publisher ID: 958

DOI: 10.1038/s10038-021-00958-2

PMC ID: 8727285

PubMed ID: 34230590

SO-VID: 97c06557-af9f-4ee6-abd0-1883775ca7cd

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 21 December 2020

Date revision received : 11 June 2021

Date accepted : 23 June 2021

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ScienceOpen disciplines: Genetics

Keywords: malaria,genetic association study

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ScienceOpen disciplines: Genetics

Keywords: malaria, genetic association study

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Human genetic variant E756del in the ion channel PIEZO1 not associated with protection from severe malaria in a large Ghanaian study

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Abstract

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Malaria vaccine development

Most cited references 8

Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection

Insights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania

Hemoglobin variants and disease manifestations in severe falciparum malaria.

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