The haptoglobin 2-2 genotype is associated with a reduced incidence of Plasmodium falciparum malaria in children on the coast of Kenya

Abstract

Background: Haptoglobin (Hp) genotype determines the efficiency of hemoglobin clearance after malaria-induced hemolysis and alters antioxidant and immune functions. The Hp2 allele is thought to have spread under strong selection pressure, but it is unclear whether this is due to protection from malaria or other diseases.

Methods: We monitored the incidence of febrile malaria and other childhood illnesses with regard to Hp genotype in a prospective cohort of 312 Kenyan children during 558.3 child-years of follow-up. We also conducted 7 cross-sectional surveys to determine the prevalence of Plasmodium falciparum parasitemia.

Results: The Hp2/2 genotype was associated with a 30% reduction in clinical malarial episodes (adjusted incidence rate ratio, 0.67; P=.008 for Hp2/2 vs. Hp1/1 and Hp2/1 combined). Protection increased with age; there was no protection in the first 2 years of life, 30% protection at > or = 2 years of age, and 50% protection from 4-10 years of age. Children with the Hp1/1 genotype had a significantly lower rate of nonmalarial fever (P=.001).

Conclusions: Balancing selection pressures may have influenced the spread of the Hp gene. Our observations suggest that the Hp2 allele may have spread as a result of protection from malaria, and the Hp1 allele may be sustained by protection from other infections.

Figure 1

Construction of a study of the incidence of Plasmodium falciparum malaria among children on the coast of Kenya.

Figure 2

Incidence rate ratios (IRRs) for clinical malaria in children with haptoglobin (Hp)^2/2 versus the Hp^1/1 and Hp^2/1 genotypes combined, by age. Because this was a longitudinal cohort study, some children contributed data to >1 age stratum. Adjusted IRRs for malaria in children with Hp^2/2, compared with baseline (individuals with Hp^1-1 and those with Hp^2-1) were calculated individually for each age stratum using a Poisson regression model, which included each definition of malaria as a dependent variable and the explanatory variables hemoglobin type (HbAA or HbAS), α⁺-thalassaemia genotype, season (defined as 3-month blocks), sex, ethnic group, and age (as a continuous variable). Ninety-five percent CIs and significance values were adjusted to take account of potential within-subject clustering of events using the sandwich estimator [32].

Figure 3

Geometric mean parasite densities, by haptoglobin (Hp) genotype. The data on asymptomatic parasitemia derive from 7 cross-sectional surveys of malaria parasite prevalence in the study cohort. The data on Hp^1-1 and Hp^2-1 reflect 291 slides that tested positive for malaria parasites (of 1197 blood slides) among 233 children, and the data for Hp^2-2 reflect 85 slides that tested positive for malaria parasites (of 428 blood slides) among 79 children. The data on clinical malaria derive from episodes of malaria (defined as an axillary temperature of >37.5°C in association with a slide positive for blood-stage asexual Plasmodium falciparum at any parasite density) detected during active and passive surveillance over 558.3 child-years of follow-up. The data on Hp^1-1 and Hp^2-1 reflects 964 episodes of malaria in 233 children, and data on Hp^2-2 reflects 280 episodes of malaria among 79 children. Comparisons were made by linear regression with adjustment for the effects of age, season, sex, ethnic group, hemoglobin type (HbAA or HbAS) and α⁺-thalassaemia genotype. For asymptomatic parasitemia, the coefficient was 0.026 (95% CI, −0.20 to 0.25; P = .82), and for clinical malaria, the coefficient was −0.08 (95% CI, −0.22 to 0.06, P = .24). Bars 95% CIs.