Article
Epistatis between the effects of sickle cell trait and a+-thalassaemia on the risk of malaria
Epistasis zwischen den Effekten der heterozygoten Sicheizellanämie und a+-Thalassämie auf das Malariarisiko
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Published: | June 2, 2010 |
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Objectives: Recently, antagonistic epistasis between the malaria-protective effects of sickle-cell-trait and a+-thalasaemia has been shown. It has been discussed that this genetic interaction might help to understand the global distribution of the sickle cell polymorphism. The aim of the study presented here was to analyse possible interactions between the effects of haemoglobin S (HbS), HbC and a+-thalasaemia (-a) on mild malaria, parasitaemia and anaemia.
Methods: In a longitudinal study 1,070 children were followed by active and passive visits from three months to 24 months of age. The effects of HbS, HbC and -a on the incidence of malaria, parasitaemia and anaemia were calculated as incidence rate ratios (IRR) with Poisson regression. Genetic effect modification between b-globin and a-globin genotypes was assessed by Wald tests.
Results: As expected, children with sickle cell trait were protected against malaria in univariate analyses. This was not the case for children with HbC and a+-thalasaemia. Considering a model with statistical interaction between the effects of b-globin and a-globin variants a trend for an antagonistic epistasis against the protection by HbAS was seen (IRR HbAS plus aa/aa 0.76, CI 0.63–0.93; IRR HbAS plus -a/aa 0.82, CI 0.58–1.16). In contrast, there was an agonistic effect on HbAC toward a susceptibility for malaria episodes (IRR HbAC plus aa/aa 0.98, CI 0.82–1.18; IRR HbAC plus -a/aa 1.43, CI 1.11–1.84).
Conclusions: Many past studies have analysed the effects of single gene variants on the risk of malaria without considering possible interactions with the effects of other polymorphisms. In this study we demonstrate the difficulties in the analysis of epistatic effects which might explain why this field is so understudied. At the same time, our data, together with data from other recent studies, indicate that epistasis between different gene variants has probably incorrectly been ignored. Further studies in this field are needed and might help to explain conflicting results on malaria protection by HbS, HbC and -a in the past.