α ⁺ -Thalassemia protects children against disease caused by other infections as well as malaria

Abstract

In the South West Pacific region, the striking geographical correlation between the frequency of ␣ ؉ -thalassemia and the endemicity of Plasmodium falciparum suggests that this hemoglobinopathy provides a selective advantage against malaria. In Vanuatu, paradoxically, ␣ ؉ -thalassemia increases the incidence of contracting mild malaria in the first 2 years of life, but severe disease was too uncommon to assess adequately. Therefore, we undertook a prospective case-control study of children with severe malaria on the north coast of Papua New Guinea, where malaria transmission is intense and ␣ ؉ -thalassemia affects more than 90% of the population. Compared with normal children, the risk of having severe malaria was 0.40 (95% confidence interval 0.22-0.74) in ␣ ؉ -thalassemia homozygotes and 0.66 (0.37-1.20) in heterozygotes. Unexpectedly, the risk of hospital admission with infections other than malaria also was reduced to a similar degree in homozygous (0.36; 95% confidence interval 0.22-0.60) and heterozygous (0.63; 0.38-1.07) children. This clinical study demonstrates that a malaria resistance gene protects against disease caused by infections other than malaria. The mechanism of the remarkable protective effect of ␣ ؉ -thalassemia against severe childhood disease remains unclear but must encompass the clear interaction between this hemoglobinopathy and both malarial and nonmalarial infections.

Phenotypic expression of pyruvate kinase deficiency and protection against malaria in a mouse model

“…HbS, HbE, and the b-thalassemias appear to be protective against malaria in the heterozygous state, while for a þ -thalassemia and the HbC (b 6Glu-Lys ) variant, protection against malaria is seen in both heterozygotes and homozygotes, and is most pronounced in homozygotes. 26,27 In the case of HbC, the mechanism of protection has been associated with reduced permissiveness of HbC erythrocytes to parasite replication. 28 G6PD deficiency, which can result in stress-induced hemolysis, also appears to protect against malaria in the heterozygous and hemizygous states.…”

Complex genetic control of susceptibility to malaria in mice

“…18 In sickle-cell anemia, heterozygosity for mutant hemoglobin alleles confers survival advantage over homozygosity for either mutant or wild type alleles. [19][20][21][22] Likewise, a protective effect against malaria has been associated with ␣ and ␤ thalassemias [23][24][25] and glucose-6-phosphate dehydrogenase deficiencies. 26,27 Finally, population-based association studies have detected several proteins that may play an important role in parasite invasion and host response to malaria.…”

Evolution of Haemoglobin Function: Molecular Adaptations to Environment

“…2,3 In the case of sickle cell Hb, or in the thalassaemias where there is an imbalance in the ratio of globin chains, the mutations are maintained in populations through natural selection by indirectly protecting the carrier against malaria or other infections. 4,5 Haemoglobin-Howick is one of about 50 mutations found in the Australasian region. 6 Here, a glycine has been substituted for a tryptophan at a locus close to the ␣-␤ contact, destabilizing the deoxy-Hb structure with the result that the blood has a high affinity for oxygen, decreased cooperativity and reduced sensitivity to pH (Bohr effect) and DPG.…”