The Dantu blood group prevents parasite growth in vivo: Evidence from a controlled human malaria infection study
- Centre for Geographic Medicine Research (Coast), KEMRI-Wellcome Trust Research Programme, Kenya
- Sanaria Incorporate, United States
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, United Kingdom
- Cambridge Institute for Medical Research, University of Cambridge, United Kingdom
- Institute for Global Health Innovation, Department of Surgery and Cancer, Imperial College London, United Kingdom
Figures
Figure 1
Study design and participant recruitment.
Figure 2
The impact of human genotype on parasite growth.
Following inoculation of volunteers with Pf sporozoites, parasitaemia was monitored by quantitative PCR (y-axis) over the full duration of the study (x-axis). The different panels indicate the specific variants that were studied. The red dots indicate only the individuals that exhibited febrile symptoms and met treatment criteria. The different genotype groups for all the variants are categorised as ‘Homozygous reference’ for individuals with two copies of the reference allele (red lines), ‘Heterozygous’ for individuals with one copy of the reference allele and one copy of the derived allele (green lines), and ‘Homozygous derived’ for individuals with two copies of the derived allele (blue lines). αα/αα, no α-thalassaemia; −α/αα, heterozygous α-thalassaemia; −α/−α, homozygous α-thalassaemia. * For G6PD, male and female were combined as C/CC = normal (wild type hemizygous males and homozygous females), CT = carrier females, and T/TT = G6PD-deficient hemizygous males and homozygous females. All volunteers were typed for all variants, and any one individual may carry a mixture of genotypes – the potential confounding effect of this was controlled for in multivariate analysis. The tables adjacent to each plot show the results from Fisher’s exact tests investigating differences in the proportion of participants that reached the pre-defined treatment threshold of 500 parasites/μl (n) compared to the total number within each genotype category (N).
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Figure 2—source data 1
Related to Figure 2.
- https://cdn.elifesciences.org/articles/83874/elife-83874-fig2-data1-v1.txt
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Figure 2—source data 2
Related to Figure 2 table.
- https://cdn.elifesciences.org/articles/83874/elife-83874-fig2-data2-v1.xlsx
Figure 3 with 1 supplement
The impact of each gene variant on the requirement for malaria treatment.
The proportion of individuals in each genotype category that required treatment over the course of the controlled human malaria infection (CHMI) study is shown on the y-axis. The number of treated individuals out of the total number in each genotype group is given in parenthesis above the bar graphs, while the p values from the Fisher’s exact tests comparing the differences in proportions of individuals that required treatment across genotype groups are also given above the bar graphs.
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Figure 3—source data 1
Related to Figure 2.
- https://cdn.elifesciences.org/articles/83874/elife-83874-fig3-data1-v1.txt
Figure 3—figure supplement 1
No differences in anti-schizont antibody levels were found across Dantu genotype groups.
The log-transformed anti-schizont antibody data were compared across Dantu genotype groups using a multivariate model with adjustments for other variant genotypes and location of residence.
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Figure 3—figure supplement 1—source data 1
Related to Figure 3—figure supplement 1.
- https://cdn.elifesciences.org/articles/83874/elife-83874-fig3-figsupp1-data1-v1.txt
Figure 4
Peak parasitaemias were lower in Dantu variant carriers.
Maximum parasitaemia values for individuals across Dantu genotype groups, with dashed line indicating the treatment threshold of 500 parasites/μl. The table below the figure shows the numbers and frequencies of individuals in each genotype category that were PCR-positive over the course of the controlled human malaria infection (CHMI) study. n = the number of participants that were PCR-positive; N = the total number within the genotype category. Statistical comparisons of proportions of PCR-positive individuals across genotype groups and pairwise comparisons between genotype groups were performed using the Fisher’s exact test. Statistical comparisons of maximum and median parasitaemia between genotype groups were performed using the Kruskal–Wallis test, and post-hoc Dunn’s test for pairwise differences between the genotype groups.
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Figure 4—source data 1
Related to Figure 4.
- https://cdn.elifesciences.org/articles/83874/elife-83874-fig4-data1-v1.txt
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Figure 4—source data 2
Related to Figure 4 table.
- https://cdn.elifesciences.org/articles/83874/elife-83874-fig4-data2-v1.xlsx
Figure 5
Time to treatment was longer in Dantu variant carriers.
The impact of each gene variant on time to treatment was analysed by (a) Kaplan–Meier survival curves, with univariate comparisons across genotype groups performed using the Log-Rank test and (b) multivariate Cox regression models, with each variant genotype coded as zero, one, or two copies of the homozygous derived allele in an additive model, adjusting for the other four malaria-protective variants, anti-schizont antibody concentration, and location of residence. Pairwise analysis compared the time to treatment in the heterozygous- and homozygous-derived genotypes to the homozygous reference genotype.
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Figure 5—source data 1
Related to Figure 5a.
- https://cdn.elifesciences.org/articles/83874/elife-83874-fig5-data1-v1.txt
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Figure 5—source data 2
Related to Figure 5b.
- https://cdn.elifesciences.org/articles/83874/elife-83874-fig5-data2-v1.txt
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Figure 5—source data 3
Related to Figure 5b table.
- https://cdn.elifesciences.org/articles/83874/elife-83874-fig5-data3-v1.xlsx
Tables
Table 1
The proportion of participants reaching the pre-defined treatment parasitaemia threshold of 500 parasites/μl by genotype category.
| Variant | Genotype | n/N | % | p value overall | p value homozygous reference vs. heterozygous | p value homozygous reference vs. homozygous derived |
|---|---|---|---|---|---|---|
| Dantu rs186873296 | Non-Dantu (AA) | 25/111 | 22.5 | 0.01 | 0.004 | 1 |
| Heterozygous (AG) | 0/27 | 0.0 | ||||
| Dantu homozygous (GG) | 0/3 | 0.0 | ||||
| G6PD +202 rs1050828 | Homozygous reference (C/CC) | 20/110 | 18.2 | 0.505 | 0.739 | 0.463 |
| Heterozygous (CT) | 4/17 | 23.5 | ||||
| Homozygous derived (T/TT) | 1/15 | 6.7 | ||||
| ABO rs8176719 | Non-O | 13/64 | 20.3 | 0.517 | 0.517 | - |
| O | 12/75 | 16.0 | ||||
| α-thalassaemia | Homozygous reference (αα/αα) | 6/48 | 12.5 | 0.408 | 0.328 | 0.29 |
| Heterozygous (−α/αα) | 14/70 | 20.0 | ||||
| Homozygous derived (−α/−α) | 5/21 | 23.8 | ||||
| ATP2B4 rs4951074 | Homozygous reference (GG) | 11/62 | 17.7 | 0.876 | 1 | 0.749 |
| Heterozygous (AG) | 11/57 | 19.3 | ||||
| Homozygous derived (AA) | 3/23 | 13.0 |
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n = the number of participants that reached the pre-defined treatment threshold of 500 parasites/μl and were treated; N = the total number within each genotype category; αα/αα, no α-thalassaemia; −α/αα, heterozygous α-thalassaemia; −α/−α, homozygous α-thalassaemia. * For G6PD, male and female were combined as C/CC = normal (wild type hemizygous males and homozygous females), CT = carrier females, and T/TT = G6PD -deficient hemizygous males and homozygous females. We used the Fisher’s exact test to investigate differences in the proportions of individuals that reached the pre-defined treatment threshold of 500 parasites/μl, both for global comparisons across genotype groups, and for separate comparisons between genotype pairs, where the proportion of individuals that reached the treatment threshold of 500 parasites/μl in the heterozygous- and homozygous -derived genotypes were compared to the homozygous reference genotype.
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Table 1—source data 1
Related to Table 1.
- https://cdn.elifesciences.org/articles/83874/elife-83874-table1-data1-v1.txt
Table 2
The numbers and frequencies of individuals who received treatment before day 21 by genotypic category.
| Variant | Genotype | n/N | % | Overall p value | Homozygous reference vs. heterozygous | Homozygous reference vs. homozygous derived |
|---|---|---|---|---|---|---|
| Dantu rs186873296 | Non-Dantu (AA) | 49/111 | 44.1 | 0.10 | 0.13 | 0.26 |
| Heterozygous (AG) | 7/27 | 25.9 | ||||
| Dantu homozygous (GG) | 0/3 | 0.0 | ||||
| G6PD +202 rs1050828* | Homozygous reference (C/CC) | 46/110 | 41.8 | 0.28 | 1.00 | 0.16 |
| Heterozygous (CT) | 7/17 | 41.2 | ||||
| Homozygous derived (T/TT) | 3/15 | 20.0 | ||||
| ABO rs8176719 | Non-O | 28/64 | 43.8 | 0.39 | - | 0.39 |
| O | 27/75 | 36.0 | ||||
| α-thalassaemia | Homozygous reference (αα/αα) | 19/48 | 39.6 | 0.79 | 0.85 | 0.79 |
| Heterozygous (−α/αα) | 30/70 | 42.9 | ||||
| Homozygous derived (−α/−α) | 7/21 | 33.3 | ||||
| ATP2B4 rs4951074 | Homozygous reference (GG) | 26/62 | 41.9 | 0.61 | 1.00 | 0.45 |
| Heterozygous (AG) | 23/57 | 40.4 | ||||
| Homozygous derived (AA) | 7/23 | 30.4 |
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Table 2—source data 1
Related to Table 2.
- https://cdn.elifesciences.org/articles/83874/elife-83874-table2-data1-v1.txt
Table 3
The association between each gene variant and the requirement for treatment after challenge.
| Overall comparison across genotype groups | Homozygous reference vs. heterozygous | Homozygous reference vs. homozygous derived | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Variant | Odds ratios | 95% CI | p-value | Odds ratios | 95% CI | p value | Odds ratios | 95% CI | p value |
| Dantu rs186873296 | 0.17 | 0.04–0.55 | 0.007 | 0.20 | 0.04–0.83 | 0.039 | 0 | NA – Inf | 0.990 |
| G6PD +202 rs1050828 | 0.60 | 0.28–1.19 | 0.157 | 1.71 | 0.41–6.59 | 0.442 | 0.17 | 0.02–0.97 | 0.074 |
| ABO rs8176719 | 0.40 | 0.15–1.03 | 0.064 | 0.54 | 0.18–1.56 | 0.259 | - | - | - |
| α-thalassaemia | 0.91 | 0.46–1.73 | 0.766 | 0.97 | 0.31–3.04 | 0.957 | 0.87 | 0.18–3.22 | 0.758 |
| ATP2B4 rs4951074 | 0.84 | 0.43–1.63 | 0.619 | 0.53 | 0.17–1.58 | 0.266 | 0.57 | 0.10–2.58 | 0.491 |
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Table 3—source data 1
Related to Table 3.
- https://cdn.elifesciences.org/articles/83874/elife-83874-table3-data1-v1.txt
Author response table 1
| Dantu genotype group | Below 500 parasites/ul | Above 500 parasites/ul | Sum |
|---|---|---|---|
| Non-Dantu (AA) | 86 | 25 | 111 |
| Dantu Heterozygote (AG) | 27 | 0 | 27 |
| Dantu Homozygote | 3 | 0 | 3 |
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The Dantu blood group prevents parasite growth in vivo: Evidence from a controlled human malaria infection study
eLife 12:e83874.
https://doi.org/10.7554/eLife.83874
