Host genetics

Williams, Thomas N.

doi:10.1002/9781118493816.ch17

Cited by 8 publications

(6 citation statements)

References 269 publications

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“… Malaria has had a major effect on the human genome, many protective polymorphisms such as sickle cell trait having been selected to high frequencies in malaria endemic regions 1 , 2 . Recently, it was shown that the blood group variant Dantu provides 74% protection against all forms of severe malaria in homozygous individuals 3 – 5 .…”

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Red blood cell tension protects against severe malaria in the Dantu blood group

Kariuki

Marín-Menéndez

Introini

et al. 2020

Nature

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Malaria has had a major effect on the human genome, many protective polymorphisms such as sickle cell trait having been selected to high frequencies in malaria endemic regions 1 , 2 . Recently, it was shown that the blood group variant Dantu provides 74% protection against all forms of severe malaria in homozygous individuals 3 – 5 . This is a similar degree of protection to sickle cell trait and considerably greater than the best malaria vaccine, but until now the protective mechanism has been unknown. Here, we demonstrate a significant impact of Dantu on Plasmodium falciparum-merozoite RBC invasion. Dantu was associated with extensive changes to the RBC surface protein repertoire, but unexpectedly, inhibition did not correlate with specific RBC-parasite receptor-ligand interactions. By following invasion using video microscopy, we found a strong link between RBC tension and merozoite invasion and identified a tension threshold above which invasion rarely occurred, even in non-Dantu RBCs. Dantu RBCs had higher average tension, meaning that a greater proportion resisted invasion. These findings provide both an explanation for the malaria-protective effect of Dantu, and fresh insights into why the efficiency of P. falciparum invasion might vary across the heterogenous populations of RBCs both within and between individuals.

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Red blood cell tension protects against severe malaria in the Dantu blood group

Kariuki

Marín-Menéndez

Introini

et al. 2020

Nature

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“…Plasmodium falciparum malaria has been the pre-eminent cause of child morbidity and mortality in the tropics and sub-tropics for much of the last 5000 years. As a consequence, it has had a substantial impact on the human genome through the positive selection of multiple polymorphisms that confer a survival advantage against the disease [1]. The best studied affect the biology of red blood cells (RBCs), which host malaria parasites for most of their life cycle in humans, the rs334 A>T b s sickle mutation in HBB [2], a-thalassaemia [3] and blood group O [4] all being important examples.…”

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confidence: 99%

Controlled Human Malaria Infection reveals that the Dantu blood group variant provides high level protection against uncomplicated malaria

Kariuki

Macharia

Makale

et al. 2022

Preprint

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Introduction The long co-evolution of Homo sapiens and Plasmodium falciparum has resulted in the selection of numerous human genetic variants that confer an advantage against severe malaria and death. One such variant is the Dantu blood group antigen, which is associated with 74% protection against severe and complicated P. falciparum malaria infections in homozygous individuals, similar to that provided by the sickle haemoglobin allele (HbS). Recent in vitro studies suggest that Dantu exerts this protection by increasing the surface tension of red blood cells, thereby impeding the ability of P. falciparum merozoites to invade them and reducing parasite multiplication. However, no studies have yet explored this hypothesis in vivo. Methods We investigated the effect of Dantu on early phase P. falciparum (Pf) infections in a controlled human malaria infection (CHMI) study. 141 sickle negative Kenyan adults were inoculated with 3.2x103 aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge) then monitored for blood-stage parasitaemia for 21 days by quantitative polymerase chain reaction (qPCR) analysis of the 18S ribosomal RNA P. falciparum gene. The primary endpoint was blood-stage P. falciparum parasitaemia of ≥500/µl while the secondary endpoint was the receipt of antimalarial treatment in the presence of parasitaemia of any density. On study completion, all participants were genotyped both for Dantu and for four other polymorphisms that are associated with protection against severe falciparum malaria: α+-thalassaemia, blood group O, G6PD deficiency, and the rs4951074 allele in the red cell calcium transporter ATP2B4. Results The primary endpoint was reached in 25/111 (22.5%) non-Dantu subjects, in comparison to 0/27 (0%) Dantu heterozygotes and 0/3 (0.0%) Dantu homozygotes (p=0.01). Similarly, 49/111 (44.1%) non-Dantu subjects reached the secondary endpoint in comparison to only 7/27 (25.9%) and none of the 3 (0.0%) Dantu heterozygotes and homozygotes respectively (P=0.021). No significant impacts on either outcome were seen for any of the other variants under study. Conclusion This study reveals, for the first time, that the Dantu blood group is associated with high level protection against early, non-clinical, P. falciparum malaria infections in vivo. Learning more about the mechanisms involved could potentially lead to new approaches to the prevention or treatment of the disease. Our study illustrates the power of CHMI with PfSPZ Challenge for directly testing the protective impact of genotypes previously identified using other methods.

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“…The α-thalassaemias are among the commonest known genetic conditions in humans 4 . They have probably arisen because of an elevated de novo mutation rate 5,6 coupled with the fact that they confer a survival advantage against death from Plasmodium falciparum malaria [5][6][7] . As a group, the α-thalassaemias are characterized by the reduced or absent production of the essential α-globin component of normal haemoglobin 4 .…”

Section: Introductionmentioning

confidence: 99%

“…D: HBA1 and HBA2 genes showing the location of the primers used for genotyping and Sanger sequencing (see methods and Extended Data); the region of the -α -3.7I deletion; and 15 bases/features that show paralogous differences in the human reference genome between HBA1 and HBA2 sequences and used to identify the -α -3. 7 Type I breakpoint (Extended Data).…”

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confidence: 99%

Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α3.7I form of α-thalassaemia using genome-wide microarray data

et al. 2021

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Background: The -α3.7I-thalassaemia deletion is very common throughout Africa because it protects against malaria. When undertaking studies to investigate human genetic adaptations to malaria or other diseases, it is important to account for any confounding effects of α-thalassaemia to rule out spurious associations. Methods: In this study, we have used direct α-thalassaemia genotyping to understand why GWAS data from a large malaria association study in Kilifi Kenya did not identify the α-thalassaemia signal. We then explored the potential use of a number of new approaches to using GWAS data for imputing α-thalassaemia as an alternative to direct genotyping by PCR. Results: We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha (HBA) gene region, which along with a complex haplotype structure, could explain the lack of an association signal from the GWAS SNP data. Some indirect typing methods gave results that were in broad agreement with those derived from direct genotyping and could identify an association signal, but none were sufficiently accurate to allow correct interpretation compared with direct typing, leading to confusing or erroneous results. Conclusions: We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies.

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Host genetics

Cited by 8 publications

References 269 publications

Red blood cell tension protects against severe malaria in the Dantu blood group

Red blood cell tension protects against severe malaria in the Dantu blood group

Controlled Human Malaria Infection reveals that the Dantu blood group variant provides high level protection against uncomplicated malaria

Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α3.7I form of α-thalassaemia using genome-wide microarray data

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