gms | German Medical Science

50. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds)
12. Jahrestagung der Deutschen Arbeitsgemeinschaft für Epidemiologie (dae)

Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie
Deutsche Arbeitsgemeinschaft für Epidemiologie

12. bis 15.09.2005, Freiburg im Breisgau

alpha-Thalassaemia protects from severe malaria anaemia but not from other clinical forms of severe malaria

Meeting Abstract

  • Jürgen May - Bernhard Nocht Institut für Tropenmedizin Hamburg, Hamburg
  • Jenniver A. Evans - Kumasi Centre, Kumasi
  • Tsiri Agbenyega - Kumasi Centre, Kumasi
  • Rolf D. Horstmann - Bernhard Nocht Institut für Tropenmedizin Hamburg, Hamburg

Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie. Deutsche Arbeitsgemeinschaft für Epidemiologie. 50. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds), 12. Jahrestagung der Deutschen Arbeitsgemeinschaft für Epidemiologie. Freiburg im Breisgau, 12.-15.09.2005. Düsseldorf, Köln: German Medical Science; 2005. Doc05gmds608

The electronic version of this article is the complete one and can be found online at:

Published: September 8, 2005

© 2005 May et al.
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Introduction and Objectives

alpha-Thalassaemias are considered to be the most common monogenic disorders of humans. Their spatial distribution strongly suggests natural selection by malaria, which has, however, been difficult to confirm clinically [1]. However, it has proved difficult to demonstrate a protective effect of a thalassaemias against malaria on clinical grounds. Initial studies showed no effect at all, and, later, alpha-thalassaemia was found to even predispose to malaria, albeit to the mild clinical form [2]. Later, it was stated that alpha-thalassaemia does protect from severe malaria in general [3], [4], [5].

Here we show in a matched-pair case-control study including 1678 children from Ghana, West Africa, that the observed effect of heterozygous alpha-thalassaemia to protect from severe malaria is driven by protection from severe anaemia, one of the major forms of severe malaria, whereas no effect of alpha-thalassaemia on the other forms of severe malaria could be detected.

Material and Methods

Patients were recruited in the Komfo Anokye Teaching Hospital, a tertiary referral centre in Kumasi, Ghana. Severe malaria was classified according to the definitions of WHO. For each patient, a control child of the same age and sex was enrolled at the village or town quarter of residency of the patient. The control children were not younger and not more than 6 months older than the patient at the time of admission. Biological parents of patients were recruited if possible as genetic controls.

alpha-Thalassaemia was genotyped using a fluorescence-resonance-energy transfer technique on a LightTyper (Roche). The number of alpha-globin genes (HbA) was assessed by measuring the differential oligonucleotide melting from the two genes. An oligonucleotide probe which hybridized to a sequence containing 3 nucleotide mismatches in the 3`-untranslated regions of the two HbA genes allowed to estimate the copy numbers of each of them separately using a melting-curve analysis.

Odds ratios (OR) with 95% confidence intervals (CI) were calculated (STATA v8.2, StataCorp) to estimate the effect of categorical exposures. Children with sickle cell anaemia (HbSS, n=8) were excluded. Conditional logistic regression was conducted for multivariate analyses. Effects of genotypes and coefficients were log-transformed to ORs and their CIs tested under the assumption of multiplicative relationships.

In case of continuous exposures, t-tests were performed if the parameters were normally distributed and non-parametric analyses (Wilcoxon- or Kruskall-Wallis test) otherwise.

The assumption of a Hardy-Weinberg equilibrium (HWE) was tested in controls by a HWE log likelihood test. Transmission disequilibrium tests (TDT) were performed to determine deviations from random (Mendelian) transmission of parental genetic variants to affected children.


Heterozygous alpha-thalassaemia was found to significantly protect from severe and complicated malaria (OR 0.75; CI 0.60-0.93). Stratifications for the various forms of severe malaria indicated that the effect was entirely due to protection against severe anaemia (OR 0.66; CI 0.50-0.88). No evidence was obtained for protection against any other malaria complication including cerebral malaria, prostration, respiratory distress, hyperparasitaemia, hyperlactataemia and acidosis.

The effect of the sickle-cell mutation HbS was analyzed for a comparison with that of alpha-thalassaemia. High degrees of protection were seen in the entire group as well as in the various subgroups whereby no indication was found for an exceptional role of severe anemia

In order to rule out misinterpretations due to unrecognized population admixtures, the association between heterozygous alpha-thalassaemia and severe malaria anaemia was subjected to a transmission disequilibrium test. With 84 observed vs. 101.5 expected transmissions of alpha-thalassaemia alleles to children with severe malaria anaemia, the protective effect was confirmed with p<0.02.


Our findings show, first, that heterozygote alpha-thalassaemia protects children from severe malaria. The results confirm a recent observation in northern Ghana and is in agreement with an earlier study in Papua New Guinea, which had shown significant protection by homozygote alpha-thalassaemia and a trend towards protection by heterozygote alpha-thalassaemia [4]. The fact that only findings with homozygote alpha-thalassaemia reached statistical significance in Papua New Guinea and only those with heterozygote alpha-thalassaemia did so in Ghana [5] corresponds to the local prevalences of the respective genotypes. Only the frequent genotypes were found in the study groups in sufficient numbers to yield significant data.

Our data show a remarkable specificity of malaria protection conferred by alpha-thalassaemia. The effect was clearly limited to severe anaemia, the most prevalent malaria complication. Protection against other malaria complications was found only when these were accompanied by severe anaemia.

The finding that alpha-thalassaemia does not protect from cerebral malaria is supported by the results of the Papua New Guinea study, although in that study no distinction had been made as to concomitant anaemia [4].

Concerning differences in malaria protection by alpha-thalasaemia and HbS, our data support previous findings. HbAS has consistently been found to reduce the frequencies of all major complications and to reduce parasite densities in these conditions. In-vitro studies have indicated that HbAS erythrocytes impair the ability of the malaria parasite Plasmodium falciparum to grow and multiply whereas thalassaemic cells have been found not to do so.

Whatever the mechanism may be our findings emphasize that there are substantial differences in the protective effects of the sickle cell trait and alpha-thalassaemia, and, furthermore, they indicate a major difference in the pathogenesis between severe anaemia and other malaria complications.


We are indepted to the participating children and their parents and guardians. We thank Mbort Attan-Ayibo, David Sambian and Jürgen Sievertsen for expert technical assistance and Lydia Nana Badu, Sophia Opoku and Christiana Tenkorang for their dedication to find control children and parents and motivate them to donate a small blood sample. The study was supported by the German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN). The Department of Child Health at Komfo Anokye Teaching Hospital is a member of the Severe Malaria in African Children Network (SMAC). Members of the SMAC team are Daniel Ansong, Sampson Antwi, Emanuel Asafo-Adjei, Samuel Blay Nguah, Kingsley Osei Kwakye, Alex Osei Yaw Akoto, Justice Sylverken.


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