Genetic Determinants of Anti-Malarial Acquired Immunity
Genetic Determinants of Anti-Malarial Acquired Immunity
Despite many years of research and intervention, malaria remains a major global health concern. Approximately half of the world's population is at risk, and in 2013 there were 207 million estimated cases of malaria and 627,000 deaths. Malaria has been described as the strongest evolutionary force in the recent history of the human genome (reviewed in) 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; however, there is also evidence to suggest that genetic factors influencing humoral immune responses may account for differences in susceptibility to malaria.
A number of studies have investigated the heritability of antibody responses against specific malaria antigens. For example, Sjoberg et al. found that antibody response to ring-infected erythrocyte surface antigen (RESA) is more concordant between monozygotic twins than either dizygotic twins or age- and sex-matched siblings in Liberia and Madagascar. In Burkina Faso sibling correlations were observed for IgG and IgG subclass responses to RESA, merozoite surface protein 1 (MSP1), MSP2 and Plasmodium falciparum extract, whilst parent-offspring correlations were observed for IgG responses to MSP2. 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.
Genetic variability in host immune response genes may account for differences in susceptibility to malaria between sympatric ethnic groups. For example, Luoni et al. found in Mali that the IL4-524 T allele, associated with immunoglobulin (Ig) switching from IgG/IgM to IgE, is significantly more common in Fulani than in Mossi or Rimaibe and is associated with significantly higher IgG levels to CSP and Pf332 malaria antigens. Also in Mali, differences in IgG sub-class levels have been seen between the Fulani and Dogon for the immunoglobulin receptor FcRIIa 131 (R/H) and the IL4-590 polymorphisms.
Many such immune-epidemiological studies are country-specific and have involved relatively small sample sizes providing different lines of evidence that have not always been independently replicated. To address this problem a large multi-centre study was undertaken to explore the associations between host genetic factors and their immune responses to malaria antigens at ten locations in Senegal, Mali (2 sites), Burkina Faso, Sudan, Kenya, Tanzania (3 sites), and Sri Lanka. Each site provided serum, DNA and clinical data. Standardized methods were used to genotype 202 polymorphisms (with previous malaria or antibody associations) and four IgG antibody levels to the malaria antigens AMA1, MSP1, MSP2, (NANP)4, plus total IgE levels. Despite the challenges of combining data from these heterogeneous study designs and backgrounds, a resource of 13,299 individuals was created to look for consistent genetic effects on anti-malarial antibodies.
Background
Despite many years of research and intervention, malaria remains a major global health concern. Approximately half of the world's population is at risk, and in 2013 there were 207 million estimated cases of malaria and 627,000 deaths. Malaria has been described as the strongest evolutionary force in the recent history of the human genome (reviewed in) 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; however, there is also evidence to suggest that genetic factors influencing humoral immune responses may account for differences in susceptibility to malaria.
A number of studies have investigated the heritability of antibody responses against specific malaria antigens. For example, Sjoberg et al. found that antibody response to ring-infected erythrocyte surface antigen (RESA) is more concordant between monozygotic twins than either dizygotic twins or age- and sex-matched siblings in Liberia and Madagascar. In Burkina Faso sibling correlations were observed for IgG and IgG subclass responses to RESA, merozoite surface protein 1 (MSP1), MSP2 and Plasmodium falciparum extract, whilst parent-offspring correlations were observed for IgG responses to MSP2. 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.
Genetic variability in host immune response genes may account for differences in susceptibility to malaria between sympatric ethnic groups. For example, Luoni et al. found in Mali that the IL4-524 T allele, associated with immunoglobulin (Ig) switching from IgG/IgM to IgE, is significantly more common in Fulani than in Mossi or Rimaibe and is associated with significantly higher IgG levels to CSP and Pf332 malaria antigens. Also in Mali, differences in IgG sub-class levels have been seen between the Fulani and Dogon for the immunoglobulin receptor FcRIIa 131 (R/H) and the IL4-590 polymorphisms.
Many such immune-epidemiological studies are country-specific and have involved relatively small sample sizes providing different lines of evidence that have not always been independently replicated. To address this problem a large multi-centre study was undertaken to explore the associations between host genetic factors and their immune responses to malaria antigens at ten locations in Senegal, Mali (2 sites), Burkina Faso, Sudan, Kenya, Tanzania (3 sites), and Sri Lanka. Each site provided serum, DNA and clinical data. Standardized methods were used to genotype 202 polymorphisms (with previous malaria or antibody associations) and four IgG antibody levels to the malaria antigens AMA1, MSP1, MSP2, (NANP)4, plus total IgE levels. Despite the challenges of combining data from these heterogeneous study designs and backgrounds, a resource of 13,299 individuals was created to look for consistent genetic effects on anti-malarial antibodies.
