Associations between red blood cell variants and malaria among children and adults from three areas of Uganda: a prospective cohort study

Elijah Kakande,Emmanuel Arinaitwe,Isabel Rodriguez-Barraquer,John Rek,Grant Dorsey,Samuel L Nsobya,Agaba Katureebe,Joaniter I Nankabirwa,Francis Bajunirwe,Moses R Kamya,Philip J Rosenthal,Andrew Walakira,Bryan Greenhouse,Chris Drakeley

doi:10.1186/s12936-020-3105-3

Abstract

BackgroundMultiple red blood cell (RBC) variants appear to offer protection against the most severe forms of Plasmodium falciparum malaria. Associations between these variants and uncomplicated malaria are less clear.MethodsData from a longitudinal cohort study conducted in 3 sub-counties in Uganda was used to quantify associations between three red blood cell variants Hb [AA, AS, S (rs334)], alpha thalassaemia 3.7 kb deletion, and glucose-6-phosphate dehydrogenase deficiency A—(G6PD 202A genotype) and malaria incidence, parasite prevalence, parasite density (a measure of anti-parasite immunity) and body temperature adjusted for parasite density (a measure of anti-disease immunity). All analyses were adjusted for age, average household entomological inoculation rate, and study site. Results for all variants were compared to those for wild type genotypes.ResultsIn children, HbAS was associated, compared to wild type, with a lower incidence of malaria (IRR = 0.78, 95% CI 0.66–0.92, p = 0.003), lower parasite density upon infection (PR = 0.66, 95% CI 0.51–0.85, p = 0.001), and lower body temperature for any given parasite density (− 0.13 ℃, 95% CI − 0.21, − 0.05, p = 0.002). In children, HbSS was associated with a lower incidence of malaria (IRR = 0.17, 95% CI 0.04–0.71, p = 0.02) and lower parasite density upon infection (PR = 0.31, 95% CI 0.18–0.54, p < 0.001). α−/αα thalassaemia, was associated with higher parasite prevalence in both children and adults (RR = 1.23, 95% CI 1.06–1.43, p = 0.008 and RR = 1.52, 95% CI 1.04–2.23, p = 0.03, respectively). G6PD deficiency was associated with lower body temperature for any given parasite density only among male hemizygote children (− 0.19 ℃, 95% CI − 0.31, − 0.06, p = 0.003).ConclusionRBC variants were associated with non-severe malaria outcomes. Elucidation of the mechanisms by which they confer protection will improve understanding of genetic protection against malaria.

Highlights

Multiple red blood cell (RBC) variants appear to offer protection against the most severe forms of Plasmodium falciparum malaria
The prevalence of all 3 red blood cell variants, Hb variant, alpha thalassaemia, and glucose-6-phosphate dehydrogenase (G6PD) deficiency were highly variable across the three sites with Nagongera having the highest prevalence and Kihihi the lowest (Additional file 1: Table S1)
haemoglobin AS geno‐ type (HbAS) was associated with a 22% lower incidence of malaria (IRR = 0.78, 95% CI 0.66–0.92, p = 0.003) and haemoglobin SS genotype (HbSS) with an 83% lower incidence of malaria (IRR = 0.17, 95% CI 0.04–0.71, p = 0.02), compared to children with wild type genotypes (Table 2)

Summary

Introduction

Multiple red blood cell (RBC) variants appear to offer protection against the most severe forms of Plasmodium falciparum malaria. Associations between these variants and uncomplicated malaria are less clear. Some studies reported that G6PD protects both heterozygous females and hemizygous males from severe malaria [9], others reported protection for only hemizygous males [10], and others reported no protection [8] Mechanisms through which these variants confer protection appear to be complex and may include restriction of red blood cell invasion and intracellular growth, increased destruction of parasitized red cells, and improved cell mediated and humoral immune responses [11,12,13,14,15,16,17]

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Conclusion