Seasonal childhood anaemia in West Africa is associated with the haptoglobin 2-2 genotype

Abstract

Background: Anaemia is a major cause of morbidity and mortality for children in Africa. The plasma protein haptoglobin (Hp) binds avidly to free haemoglobin released following malaria-induced haemolysis. Haptoglobin polymorphisms result in proteins with altered haemoglobin-binding capacity and different antioxidant, iron-recycling, and immune functions. Previous studies examined the importance of haptoglobin polymorphism in malaria and iron homeostasis, but it is unknown whether haptoglobin genotype might be a risk factor for anaemia in children in a malaria-endemic area.

Methods and findings: A cohort of 780 rural Gambian children aged 2-6 y was surveyed at the start and end of the malaria season. Samples were taken to assess haemoglobin (Hb) concentration, iron status (ferritin, zinc protoporphyrin, transferrin saturation, and soluble transferrin receptor concentration), haptoglobin concentration, alpha-1-antichymotrypsin (a measure of inflammation), and malaria parasites on blood film. We extracted DNA and genotyped for haptoglobin, sickle cell, and glucose-6-phosphate (G6PD) deficiency. Mean Hb levels fell over the malaria season. Children with the haptoglobin 2-2 genotype (17%) had a greater mean drop in Hb level over the malaria season (an 8.9 g/l drop; confidence interval [CI] 5.7, 12.1) compared to other children (a 5.1 g/l drop; CI 3.8, 6.4). In multivariate regression analysis, controlling for baseline Hb level, age group, village, malaria parasites on blood film, iron status, haptoglobin concentration, and G6PD deficiency, haptoglobin genotype predicted Hb level at the end of the malaria season (p = 0.0009, coefficient = -4.2). Iron status was not influenced by haptoglobin genotype.

Conclusions: The finding that haptoglobin 2-2 genotype is a risk factor for anaemia in children in a malaria-endemic area may reflect the reduced ability of the Hp2-2 polymer to scavenge free haemoglobin-iron following malaria-induced haemolysis. The magnitude of the effect of haptoglobin genotype (4 g/l Hb difference, p = 0.0009) was comparable to that of G6PD deficiency or HbAS (3 g/l difference, p = 0.03; and 2 g/l difference, p = 0.68, respectively).

Figure 1. Sample Construction

At the start of the malaria season, 780 children (aged 2–6 y) were recruited from ten rural Gambian villages, of these, 61 children were lost to follow-up (of whom four died). At the end of the malaria season, 707 children were surveyed. A total of 671 children had complete haemoglobin, malaria blood film, and haptoglobin genotype data. After biochemical assays and further genotyping, 565 children had complete data for multivariate regression analysis.

Figure 2. Drop in Haemoglobin Level during the Malaria Season according to HbAS, G6PD Deficiency, and Haptoglobin Genotype

Haemoglobin levels at the start and end of the malaria season are shown by haptoglobin genotype ( Hp ^2/2 versus Hp ^1/1 and Hp ^1/2 combined), HbAS compared to HbAA and G6PD (A type) deficiency, wild-type, heterozygotes, and homozygotes/hemizygotes. Error bars denote standard error of the mean.