Associations between erythrocyte polymorphisms and risks of uncomplicated and severe malaria in Ugandan children: A case control study.
Level 4 - case-series / case-control
Age-matched three-arm case-control study
PubMed 30222732 · doi:10.1371/journal.pone.0203229
What was done
A three-arm age-matched case-control study evaluated 975 Ugandan children: 325 with severe malaria, 325 with uncomplicated malaria, and 325 healthy community controls. Molecular methods determined hemoglobin variants (including HbAS), alpha-thalassemia genotypes (-alpha/-alpha and -alpha/alpha alpha), and G6PD deficiency. Conditional logistic regression estimated odds ratios (ORs) for associations with uncomplicated malaria, severe malaria overall, and specific severe malaria clinical phenotypes (severe anemia and altered consciousness).
What was found
No tested polymorphism protected against uncomplicated malaria; alpha-thalassemia homozygotes (-alpha/-alpha) had increased uncomplicated malaria risk (OR 2.40; 95% CI 1.15 to 5.03; p = 0.020). For severe malaria: - HbAS reduced risk compared to uncomplicated malaria controls (OR 0.46; 95% CI 0.23 to 0.95; p = 0.036) and community controls (OR 0.23; 95% CI 0.11 to 0.50; p < 0.001); this protection was specific to severe anemia (OR 0.17; 95% CI 0.04 to 0.65; p = 0.009). - Heterozygous alpha-thalassemia (-alpha/alpha alpha) protected against severe malaria vs uncomplicated malaria (OR 0.51; 95% CI 0.24 to 0.77; p = 0.001) and community controls (OR 0.49; 95% CI 0.32 to 0.76; p = 0.002); protection was specific to altered consciousness (OR 0.24; 95% CI 0.09 to 0.59; p = 0.002). - Homozygous alpha-thalassemia (-alpha/-alpha) protected against severe malaria vs uncomplicated malaria (OR 0.34; 95% CI 0.156 to 0.73; p = 0.005), but not vs community controls (OR 1.03; 95% CI 0.46 to 2.27; p = 0.935). - Negative epistasis occurred between HbAS and -alpha/alpha alpha, with no statistically significant protection in individuals carrying both (OR 0.45; 95% CI 0.11 to 1.84; p = 0.269). - G6PD deficiency was not protective against severe malaria.
Why it matters
This study demonstrates that common red blood cell polymorphisms confer protection against distinct clinical presentations of severe malaria, and that coinheritance of HbAS and alpha-thalassemia trait results in loss of protection due to negative epistasis.
Limits
As an observational case-control design, the study cannot measure direct incidence. Stratified analyses by specific severe malaria phenotypes and dual-polymorphism combinations resulted in smaller sample sizes and wide confidence intervals. Findings in Ugandan children may not generalize to other populations with different genetic backgrounds or transmission intensities.