Dominic Kwiatkowski - Big malaria study

12 October 2014

Interview with

Prof Dominic Kwiatkowski, Wellcome Trust Sanger Institute/MRC Centre for genomics and global health

Kat - This month, researchers at the University of Oxford and the Wellcome Trust Sanger Institute published results from the biggest ever study looking at how genetic variation in people affects how they respond to malaria infection. To explain more about the study, and why it was urgently needed to push forward the frontiers in the battle against this killer disease, I spoke to project leader Professor Dominic Kwiatkowski, director of the Medical Research Council's Centre for Genomics and Global Health.

Dominic -  Well, it's been known for over half a century that human genetic factors influence the outcome of malaria and indeed that malaria has been a major source of evolutionary pressure on the human genome.  And there have being a very large number of papers, hundreds of papers, published on different genetic factors that seem to influence susceptibility to malaria and in particular, influence the likelihood that a child who's living in a malaria endemic region who is repeatedly infected with malaria, the chance that the child will die or suffer life threatening complications of that infection. 

Because one of the curious things is that in areas where malaria is endemic, whilst everyone has malaria for much over time, only a certain proportion of malaria attacks are fatal.  Although a lot of studies have been published on the genetic factors, they've tended to come from relatively small studies.  And so, when you look at the literature, you find lots of reported associations.  It's very difficult to know which of them whether when you differences, whether those differences are like true biological differences or alternatively, just due to small sample size or to various factors that cause noise or to differences in assay design.

Kat -  So, with this study, how many people did you manage to get into it and what did you find?

Dominic -  Well, we managed to recruit over 12,000 cases of severe malaria - life threatening forms of malaria - from about 10 or 11 countries, together with our 17,000 population controls.  So, the total size of the study was 30,000 individuals.  What we found when we tested about 50 known loci that had been reported to determine resistance from malaria, we found that some of them were undoubtedly authentic and gave very strong and consistent effects.  It was not any surprise at all that we found very strong effects - protective effects.

Kat -  Would this be things like the sickle cell gene that we know about?

Dominic -  Exactly.  Sickle, it wasn't at all a surprise that it gave a strong effect.  I think what did pleasantly surprise us was that that effect was very strong.  It gives about 90% protection.  It was very consistent across sites and also importantly, it was consistent protection against different sorts of severe malaria.  

So children can die of malaria for multiple reasons.  One is profound coma, a syndrome known as cerebral malaria.  Another is profound anaemia.  It turned out that sickle cell gave exactly the same protection against those different outcomes.  And that, I think tells us that sickle cell is not protecting against those outcomes per se, but it's doing something for that.  It's sort of helping to reduce the infection per se and that in turn is reducing risk of its complications.  

The take-home message would be three things.  Firstly, there was a bunch of things that we knew about that replicated, I mentioned sickle, also blood group O, also a calcium channel - a gene called ATP2B4 - another thing called G6PD.  But then a whole bunch of other things that have been reported before just didn't replicate in a multi-centre analysis.  And that really showed the power of doing large studies.  It allows you to sort the wheat from the chaff.  

The third thing we found which was really important was that some of the authentic loci gave very consistent effects, but others were undoubtedly authentic, but actually get quite heterogeneous effects.  Either heterogeneous between different locations, different geographical regions or heterogeneous in their effects on different forms of severe malaria.  And the most striking example that was this genetic factor called G6PD deficiency - that's a blood disorder - which gives protection against cerebral malaria.  That's to say, coma due to malaria.  But actually, makes individuals liable to profound anaemia.  So, that was a bit of a surprise to us.

Kat -  When you think about the battle between the human genome and the malaria genome, it is a bit of an evolutionary arms race.  That tells us that it's a complicated battle going on, doesn't it?

Dominic -  Well, it does and I think that this study gives us a foundation for looking at those issues because one of the most important outcomes of that evolutionary arms race that you're talking about is going on in real time.  It means that actually, things are changing a lot in real time and so, genetic effects that may operate today in one population may not be operating in a different population at a different time because the parasite population may have changed.  But what we have here as a result of this study is a framework that we can study those heterogeneous effects with some level of scientific certainty.  

But the problem is that when we just do patchy isolated small studies.  We never know whether those differences are due to true biological heterogeneity or whether they're just the sort of noise of doing small studies which aren't particularly well-standardised.  Now, we have a framework to study that heterogeneity in considerable detail, and that's an extraordinary advance for us and for the field, we believe.

Kat - That was Dominic Kwiatkowski, from the MRC Centre for Genomics and Global Health.

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