The effect of alpha+-thalassaemia on the incidence of malaria and other diseases in children living on the coast of Kenya

Abstract

Background: The alpha-thalassaemias are the commonest genetic disorders of humans. It is generally believed that this high frequency reflects selection through a survival advantage against death from malaria; nevertheless, the epidemiological description of the relationships between alpha-thalassaemia, malaria, and other common causes of child mortality remains incomplete.

Methods and findings: We studied the alpha+-thalassaemia-specific incidence of malaria and other common childhood diseases in two cohorts of children living on the coast of Kenya. We found no associations between alpha+-thalassaemia and the prevalence of symptomless Plasmodium falciparum parasitaemia, the incidence of uncomplicated P. falciparum disease, or parasite densities during mild or severe malaria episodes. However, we found significant negative associations between alpha+-thalassaemia and the incidence rates of severe malaria and severe anaemia (haemoglobin concentration < 50 g/l). The strongest associations were for severe malaria anaemia (> 10,000 P. falciparum parasites/mul) and severe nonmalaria anaemia; the incidence rate ratios and 95% confidence intervals (CIs) for alpha+-thalassaemia heterozygotes and homozygotes combined compared to normal children were, for severe malaria anaemia, 0.33 (95% CI, 0.15,0.73; p = 0.006), and for severe nonmalaria anaemia, 0.26 (95% CI, 0.09,0.77; p = 0.015).

Conclusions: Our observations suggest, first that selection for alpha+-thalassaemia might be mediated by a specific effect against severe anaemia, an observation that may lead to fresh insights into the aetiology of this important condition. Second, although alpha+-thalassaemia is strongly protective against severe and fatal malaria, its effects are not detectable at the level of any other malaria outcome; this result provides a cautionary example for studies aimed at testing malaria interventions or identifying new malaria-protective genes.

Figure 1. Parasite Densities by Clinical Status and α ⁺-Thalassaemia Genotype

Geometric mean parasite densities are shown with 95% CIs. Data on symptomless parasitaemia reflect 59 measurements on normal (αα/αα) children, 100 on heterozygotes (−α/αα), and 23 on homozygotes (−α/−α) for α ⁺-thalassaemia. The equivalent figures for mild, hospital, and severe malaria are described in Tables 1 and 2. Between-genotype differences were tested using linear regression both with and without adjustments for age, season, and within-patient clustering. No significant differences were found.

Figure 2. Haemoglobin Concentrations at Steady State and During Episodes of Clinical P. falciparum Malaria

Values are means (with standard errors). 1 g/dl = 10 g/l Data for steady state, all malaria admissions, and severe malaria admissions derive from the birth cohort study. Severe malaria was defined as described in the text. Study participants (and genotypes) numbered as follows: steady state n = 2,104 (αα/αα, 739; −α/αα, 1,017; −α/−α, 348); all malaria admissions n = 434 (αα/αα, 174; −α/αα, 196; −α/−α, 64); and severe malaria admissions n = 146 (αα/αα, 67; −α/αα, 55; −α/−α, 24). Data for uncomplicated malaria derive from the mild disease cohort study. Data for αα/αα reflect 420 measurements in 96 study participants; for −α/αα are from 701 in 149; and for −α/−α are from 212 in 56. Amongst children in steady state, mean difference (β) = −2.6 g/l (95% CI, −4.1,−1.1; p = 0.001) and −5.6 (−7.8,− 3.8; p < 0.001) for −α/αα and −α/−α, respectively. The equivalent β values for uncomplicated malaria were −3.2 (−5.6,−7.7; p = 0.010) and −6.8 (−10,−3.4; p < 0.001); for hospital-admitted malaria were 8.4 (2.8,14.1; p = 0.003) and 0.97 (0.29,1.65; p = 0.005); and for severe malaria were 1.08 (−0.10,2.25; p = 0.072) and 13.8 (0.60,26.9; p = 0.041). These figures were adjusted for age (as continuous) and sex, and for potential within-person clustering where children contributed more than one data point.