Abstract
BackgroundIt is important to understand the extent to which genetic factors regulate acquired immunity to common infections. A classical twin study design is useful to estimate the heritable component of variation in measurable immune parameters.Methodology/Principal FindingsThis study assessed the relative heritability of different plasma antibody isotypes and subclasses (IgG1, IgG2, IgG3, IgG4, IgM, IgA and IgE) naturally acquired to P. falciparum blood stage antigens AMA1, MSP1-19, MSP2 (two allelic types) and MSP3 (two allelic types). Separate analyses were performed on plasma from 213 pairs of Gambian adult twins, 199 child twin pairs sampled in a dry season when there was little malaria transmission, and another set of 107 child twin pairs sampled at the end of the annual wet season when malaria was common. There were significantly positive heritability (h 2) estimates for 48% (20/42) of the specific antibody assays (for the seven isotypes and subclasses to the six antigens tested) among the adults, 48% (20/42) among the children in the dry season and 31% (13/42) among the children in the wet season. In children, there were significant heritability estimates for IgG4 reactivity against each of the antigens, and this subclass had higher heritability than the other subclasses and isotypes. In adults, 75% (15/20) of the significantly heritable antigen-specific isotype responses were attributable to non-HLA class II genetic variation, whereas none showed a significant HLA contribution.SignificanceGenome-wide approaches are now warranted to map the major genetic determinants of variable antibody isotype and subclass responses to malaria, alongside evaluation of their impact on infection and disease. Although plasma levels of IgG4 to malaria antigens are generally low, the exceptionally high heritability of levels of this subclass in children deserves particular investigation.
Highlights
Genetic variation among individuals profoundly affects susceptibility to clinical malaria, only a minority of the causal polymorphisms are known [1,2]
This study shows that there are differences in the heritabilities of different antibody isotype and subclass responses to malaria in children, with IgG4 having higher heritability than the other isotypes
Of different antibody isotype levels in the adults, and heritability of IgG4 levels was significantly lower in adults than in children recruited either in the dry season when malaria incidence is low or the wet season when incidence is at an annual peak
Summary
Genetic variation among individuals profoundly affects susceptibility to clinical malaria, only a minority of the causal polymorphisms are known [1,2]. An estimate of the heritability of a phenotypic trait can be derived by a Classical Twin Study (CTS) [7]. The genetic contribution to the overall variance in a phenotype can be estimated by comparing the intra-pair similarity of monozygous twins (MZ) and dizygous twins (DZ) [9], deriving an estimate of heritability (h2) [10]. Such findings may be generalised to populations if the trait is normally the same in twins and singletons, and if it has no association with zygosity or gender [7]. A classical twin study design is useful to estimate the heritable component of variation in measurable immune parameters
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