| 1. |
- Jallow, Muminatou, et al.
(författare)
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Genome-wide and fine-resolution association analysis of malaria in West Africa.
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; , s. 657-665
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Tidskriftsartikel (refereegranskat)abstract
- We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 x 10(-7) to P = 4 x 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.
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| 2. |
- Maiga, Bakary, et al.
(författare)
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Glucose-6-phosphate dehydrogenase polymorphisms and susceptibility to mild malaria in Dogon and Fulani, Mali
- 2014
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 13, s. 270-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with protection from severe malaria, and potentially uncomplicated malaria phenotypes. It has been documented that G6PD deficiency in sub-Saharan Africa is due to the 202A/376G G6PD A-allele, and association studies have used genotyping as a convenient technique for epidemiological studies. However, recent studies have shown discrepancies in G6PD202/376 associations with severe malaria. There is evidence to suggest that other G6PD deficiency alleles may be common in some regions of West Africa, and that allelic heterogeneity could explain these discrepancies. Methods: A cross-sectional epidemiological study of malaria susceptibility was conducted during 2006 and 2007 in the Sahel meso-endemic malaria zone of Mali. The study included Dogon (n = 375) and Fulani (n = 337) sympatric ethnic groups, where the latter group is characterized by lower susceptibility to Plasmodium falciparum malaria. Fifty-three G6PD polymorphisms, including 202/376, were genotyped across the 712 samples. Evidence of association of these G6PD polymorphisms and mild malaria was assessed in both ethnic groups using genotypic and haplotypic statistical tests. Results: It was confirmed that the Fulani are less susceptible to malaria, and the 202A mutation is rare in this group (< 1% versus Dogon 7.9%). The Betica-Selma 968C/376G (similar to 11% enzymatic activity) was more common in Fulani (6.1% vs Dogon 0.0%). There are differences in haplotype frequencies between Dogon and Fulani, and association analysis did not reveal strong evidence of protective G6PD genetic effects against uncomplicated malaria in both ethnic groups and gender. However, there was some evidence of increased risk of mild malaria in Dogon with the 202A mutation, attaining borderline statistical significance in females. The rs915942 polymorphism was found to be associated with asymptomatic malaria in Dogon females, and the rs61042368 polymorphism was associated with clinical malaria in Fulani males. Conclusions: The results highlight the need to consider markers in addition to G6PD202 in studies of deficiency. Further, large genetic epidemiological studies of multi-ethnic groups in West Africa across a spectrum of malaria severity phenotypes are required to establish who receives protection from G6PD deficiency.
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| 3. |
- Maiga, Bakary, et al.
(författare)
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Human Candidate Polymorphisms in Sympatric Ethnic Groups Differing in Malaria Susceptibility in Mali
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10
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Tidskriftsartikel (refereegranskat)abstract
- Malaria still remains a major public health problem in Mali, although disease susceptibility varies between ethnic groups, particularly between the Fulani and Dogon. These two sympatric groups share similar socio-cultural factors and malaria transmission rates, but Fulani individuals tend to show significantly higher spleen enlargement scores, lower parasite prevalence, and seem less affected by the disease than their Dogon neighbours. We have used genetic polymorphisms from malaria-associated genes to investigate associations with various malaria metrics between the Fulanai and Dogon groups. Two cross sectional surveys (transmission season 2006, dry season 2007) were performed. Healthy volunteers from the both ethnic groups (n=939) were recruited in a rural setting. In each survey, clinical (spleen enlargement, axillary temperature, weight) and parasitological data (malaria parasite densities and species) were collected, as well as blood samples. One hundred and sixty six SNPs were genotyped and 5 immunoassays (AMA1, CSP, MSP1, MSP2, total IgE) were performed on the DNA and serum samples respectively. The data confirm the reduced malaria susceptibility in the Fulani, with a higher level of the protective O-blood group, and increased circulating antibody levels to several malaria antigens (p<10(-15)). We identified SNP allele frequency differences between the 2 ethnic groups in CD36, IL4, RTN3 and ADCY9. Moreover, polymorphisms in FCER1A, RAD50, TNF, SLC22A4, and IL13 genes were correlated with antibody production (p-value<0.003). Further work is required to understand the mechanisms underpinning these genetic factors.
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| 4. |
- Shelton, Jennifer M. G., et al.
(författare)
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Genetic determinants of anti-malarial acquired immunity in a large multi-centre study
- 2015
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Ingår i: Malaria Journal. - : Springer Science and Business Media LLC. - 1475-2875. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels. Methods: Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP) 4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels. Results: Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)(4) epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2. Conclusion: Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity.
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