Abstract
BackgroundMany 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.MethodsSera, 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.ResultsMalaria 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.ConclusionAlthough 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0833-x) contains supplementary material, which is available to authorized users.
Highlights
Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated
Conclusion: 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
In Burkina Faso sibling correlations were observed for IgG and IgG subclass responses to ring-infected erythrocyte surface antigen (RESA), merozoite surface protein 1 (MSP1), merozoite surface protein 2 (MSP2) and Plasmodium falciparum extract, whilst parent-offspring correlations were observed for IgG responses to MSP2 [5]
Summary
Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. Malaria has been described as the strongest evolutionary force in the recent history of the human genome (reviewed in [2]) and exerts a selective pressure that has resulted in a number of genetic adaptations. These adaptations predominantly cause erythrocyte defects, which affect the binding, invasion and growth of malaria parasites; there is evidence to suggest that genetic factors influencing humoral immune responses may account for differences in susceptibility to malaria [3]. A study in Papua New Guinea found substantial heritability for IgG subclass responses to RESA and MSP2 and showed that this genetic variation was not dominated by a single major gene, suggesting multifactorial inheritance for IgG responses to malaria antigens [6,7,8]
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