Epistasis between the haptoglobin common variant and alpha+thalassemia influences risk of severe malaria in Kenyan children
Atkinson SH, Uyoga SM, Nyatichi E, Macharia AW, Nyutu G, Ndila C, Kwiatkowski DP, Rockett KA, Williams TN
Haptoglobin (Hp) scavenges free hemoglobin following malaria-induced hemolysis. Few studies have investigated the relationship between the common Hp variants and the risk of severe malaria, and their results are inconclusive. We conducted a case-control study of 996 children with severe Plasmodium falciparum malaria and 1220 community controls and genotyped for Hp, hemoglobin (Hb) S heterozygotes, and alpha(+)thalassemia. Hb S heterozygotes and alpha(+)thalassemia homozygotes were protected from severe malaria (odds ratio [OR], 0.12; 95% confidence interval [CI], 0.07-0.18 and OR, 0.69; 95% CI, 0.53-0.91, respectively). The risk of severe malaria also varied by Hp genotype: Hp2-1 was associated with the greatest protection against severe malaria and Hp2-2 with the greatest risk. Meta-analysis of the current and published studies suggests that Hp2-2 is associated with increased risk of severe malaria compared with Hp2-1. We found a significant interaction between Hp genotype and alpha(+)thalassemia in predicting risk of severe malaria: Hp2-1 in combination with heterozygous or homozygous alpha(+)thalassemia was associated with protection from severe malaria (OR, 0.73; 95% CI, 0.54-0.99 and OR, 0.48; 95% CI, 0.32-0.73, respectively), but alpha(+)thalassemia in combination with Hp2-2 was not protective. This epistatic interaction together with varying frequencies of alpha(+)thalassemia across Africa may explain the inconsistent relationship between Hp genotype and malaria reported in previous studies.