Heritability of the human infectious reservoir of malaria parasites

Abstract

Background: Studies on human genetic factors associated with malaria have hitherto concentrated on their role in susceptibility to and protection from disease. In contrast, virtually no attention has been paid to the role of human genetics in eliciting the production of parasite transmission stages, the gametocytes, and thus enhancing the spread of disease.

Methods and findings: We analysed four longitudinal family-based cohort studies from Senegal and Thailand followed for 2-8 years and evaluated the relative impact of the human genetic and non-genetic factors on gametocyte production in infections of Plasmodium falciparum or P. vivax. Prevalence and density of gametocyte carriage were evaluated in asymptomatic and symptomatic infections by examination of Giemsa-stained blood smears and/or RT-PCR (for falciparum in one site). A significant human genetic contribution was found to be associated with gametocyte prevalence in asymptomatic P. falciparum infections. By contrast, there was no heritability associated with the production of gametocytes for P. falciparum or P. vivax symptomatic infections. Sickle cell mutation, HbS, was associated with increased gametocyte prevalence but its contribution was small.

Conclusions: The existence of a significant human genetic contribution to gametocyte prevalence in asymptomatic infections suggests that candidate gene and genome wide association approaches may be usefully applied to explore the underlying human genetics. Prospective epidemiological studies will provide an opportunity to generate novel and perhaps more epidemiologically pertinent gametocyte data with which similar analyses can be performed and the role of human genetics in parasite transmission ascertained.

Figure 1. Gametocyte prevalence (line plot) and density (histogram) in symptomatic and/or asymptomatic infections by semester-year in Dielmo.

1/“year” indicates the first semester and 2/“year” the second semester of each year. Shown are means and SE for gametocyte density. Given in the boxes are the corresponding number of infections of P. falciparum and the number of these that were positive for gametocytes (and hence used to calculate the gametocyte densities).

Figure 2. Gametocyte prevalence (line plot) and density (histogram) in symptomatic and/or asymptomatic infections by semester-year in Ndiop 1/“year” indicates the first semester and 2/“year” the second semester of each year.

Shown are means and SE for gametocyte density. Given in the boxes are the corresponding number of infections of P. falciparum and the number of these that were positive for gametocytes (and hence used to calculate the gametocyte densities).

Figure 3. Gametocyte prevalence (line plot) and density (histogram) in symptomatic infections by semester-year in Suan Phung.

1/“year” indicates the first semester and 2/“year” the second semester of each year. Shown are means and SE for gametocyte density. Given in the boxes are the corresponding number of infections of P. falciparum or P. vivax and the number of these that were positive for gametocytes (and hence used to calculate the gametocyte densities).

Figure 4. Proportion of variation explained by genetic heritability and environmental factors found to have a significant effect on P. falciparum gametocyte positivity ( Table 4 & 5 ).

(A) Asymptomatic infections, Dielmo (B) Asymptomatic infections, Ndiop (C) Asymptomatic infections, Gouye Kouly (D) Symptomatic infections, Dielmo (E) Symptomatic infections, Ndiop (F) Symptomatic infections, Suan Phung. Colour coding: Brown, age; Blue, date; Green, asexual parasite density; red, human genetics; beige, other.