Heritability of the human infectious reservoir of malaria parasites.

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.

Positively selected G6PD-Mahidol mutation reduces Plasmodium vivax density in Southeast Asians.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency--the most common known enzymopathy--is associated with neonatal jaundice and hemolytic anemia usually after exposure to certain infections, foods, or medications. Although G6PD-deficient alleles appear to confer a protective effect against malaria, the link with clinical protection from Plasmodium infection remains unclear. We investigated the effect of a common G6PD deficiency variant in Southeast Asia--the G6PD-Mahidol(487A) variant--on human survival related to vivax and falciparum malaria. Our results show that strong and recent positive selection has targeted the Mahidol variant over the past 1500 years. We found that the G6PD-Mahidol(487A) variant reduces vivax, but not falciparum, parasite density in humans, which indicates that Plasmodium vivax has been a driving force behind the strong selective advantage conferred by this mutation.

Heritability of P. falciparum and P. vivax malaria in a Karen population in Thailand.

The majority of studies concerning malaria host genetics have focused on individual genes that confer protection against rather than susceptibility to malaria. Establishing the relative impact of genetic versus non-genetic factors on malaria infection and disease is essential to focus effort on key determinant factors. This relative contribution has rarely been evaluated for Plasmodium falciparum and almost never for Plasmodium vivax. We conducted a longitudinal cohort study in a Karen population of 3,484 individuals in a region of mesoendemic malaria, Thailand from 1998 to 2005. The number of P. falciparum and P. vivax clinical cases and the parasite density per person were determined. Statistical analyses were performed to account for the influence of environmental factors and the genetic heritability of the phenotypes was calculated using the pedigree-based variance components model. The genetic contribution to the number of clinical episodes resulting from P. falciparum and P. vivax were 10% and 19% respectively. There was also moderate genetic contribution to the maximum and overall parasite trophozoite density phenotypes for both P. falciparum (16%&16%) and P. vivax (15%&13%). These values, for P. falciparum, were similar to those previously observed in a region of much higher transmission intensity in Senegal, West Africa. Although environmental factors play an important role in acquiring an infection, genetics plays a determinant role in the outcome of an infection with either malaria parasite species prior to the development of immunity.

Glucose-6-phosphate dehydrogenase mutations in Mon and Burmese of southern Myanmar.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is highly prevalent in Southeast Asians. G6PD mutations are associated with specific ethnic groups in Southeast Asia. Mon is a minority ethnic group in Myanmar, which speaks Monic, a distinct language of Mon-Khmer classification. We studied G6PD mutations in Mon and Burmese males of southern Myanmar who migrated to Thailand in Samutsakhon province. G6PD deficiency was identified in 19 (12%) of 162 Mon males and 17 (10%) of 178 Burmese males, and then assayed for G6PD mutations. Among 19 G6PD-deficient Mons, 12 were G6PD Mahidol; one case each was G6PD Jammu (871G > A; nt 1311C), G6PD Kaiping (1388G > A), G6PD Mediterranean (563C > T), a novel mutation 94(C > G); and three remain unidentified. Among 17 G6PD-deficient Burmese, 12 were G6PD Mahidol; one each was G6PD Coimbra (592C > T), G6PD Kerala-Kalyan (949G > A), and G6PD Valladolid (406C > T); and two remain unidentified. G6PD Mahidol (487G > A) is the most common mutation among Mons and Burmese. All G6PD deficient Mon and Burmese, except for a person with G6PD Valladolid, shared the same haplotype nt93T, nt1311C. Despite a similar language root with Cambodian's Khmer language, our study suggests that Mon people share a common ancestry with Burmese rather than Cambodians.

G6PD Viangchan (871G>A) is the most common G6PD-deficient variant in the Cambodian population.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common hereditary enzymopathy among Southeast Asians. We studied G6PD mutations in 108 migrant Cambodian laborers in Chanthaburi province and cord blood samples from 107 Cambodian newborns at Buriram Hospital. Thirty-one (26.1%) of 119 Cambodian males and three of 96 (3.1%) females were G6PD deficient and were assayed for G6PD mutations. G6PD Viangchan (871G>A) was identified in most G6PD-deficient Cambodians (28 of 34; 82.4%); G6PD Union (1360C>T) and G6PD Coimbra (592C>T) was found in one case each. We concluded that G6PD Viangchan (871G>A) was the most common mutation among Cambodians. This finding is similar to G6PD-deficient Thais and Laotians, suggesting a common ancestry of people from these three countries.