Malaria versus the human genome 4/9/02. By Dominic Kwiatkowski Variations in human genes influence susceptibility to malaria. Professor Dominic Kwiatkowski discusses key discoveries and hopes for the future.

A few years before it was proved that genes are made of DNA – in the late 1940s – scientists began to suspect that malaria had influenced human evolution in a big way. The clues were that malaria parasites invade human red blood cells, and that diseases of red blood cells such as thalassaemia and sickle-cell anaemia, which are the commonest group of genetic disorders in humans, are mainly found in populations exposed to malaria and their descendants.

J B S Haldane proposed that such genetic diseases could have evolved through natural selection if people who inherit the genetic factor from only one parent (heterozygotes) are protected against malaria but the harmful effects are confined to the much smaller number of people who inherit the genetic factor from both parents (homozygotes).

At about the same time, Linus Pauling's lab showed that individuals with sickle-cell anaemia possess a type of haemoglobin (called HbS) that differs from the common form (called HbA), thus providing one of the first pieces of direct evidence that human genetic diseases have a molecular basis.

These days most biology students know the precise difference between HbS and HbA (a mutation that causes valine to be substituted for glutamic acid at the sixth position of the beta-globin chain), while Haldane's intuition has been proved correct by studies showing that African children who are heterozygous carriers of HbS have a ten-fold reduction in their risk of contracting life-threatening forms of malaria.

It is remarkable how many different types of genetic variation of human red blood cells appear to have evolved due to natural selection by malaria. They include thalassaemia, a common group of diseases arising from disordered regulation of haemoglobin production; HbC, another variant form of haemoglobin that protects against malaria but has fewer harmful consequences than HbS; variations in a red blood cell enzyme called glucose-6-phosphate dehydrogenase; and ovalocytosis, a defect of a structural protein that helps to maintain the normal shape of the red blood cell.

Special mention must be made of a genetic factor possessed by many Africans that suppresses the Duffy antigen (a human protein on the surface of red blood cells that in part determines blood group) and thereby protects them from developing Plasmodium vivax infection.

This is a beautiful example of how genetic epidemiology can provide fundamental insights into molecular mechanisms of disease: the simple observation that P. vivax infection is uncommon in Africa put Louis Miller and his colleagues onto a scientific trail that eventually led, via the Duffy antigen, to the discovery of parasite molecules used in the invasion of human red blood cells.

The big question, about which we still have relatively little information, is the extent to which susceptibility to malaria is determined by genetic variation in the human immune system.

This is a hugely important topic because the malaria vaccine effort is being slowed down by our poor understanding of the molecular basis of natural immunity, and one of the most effective ways of identifying critical immune mediators may be to determine how genetic variation in the corresponding genes affects susceptibility to malaria in the populations of malaria-endemic areas.

A few clues have emerged over the last 12 years, starting with studies of HLA-B – a protein that 'presents' molecules from foreign, invading organisms to the immune system, sparking an immune response. Adrian Hill discovered that a particular variant of HLA-B is present at an unusually high frequency in West Africans and is associated with protection from severe malaria in this population.

As HLA-B is expressed on liver cells and not on red blood cells, this suggests that immune mechanisms targeted against the liver stage of malaria infection are a significant factor in protection against severe malaria, so this has bolstered efforts to develop a liver-stage vaccine.

There is also evidence that the disease severity of malaria is determined by genetic factors that regulate the production of inflammatory mediators such as tumour necrosis factor and nitric oxide. These mediators are critical for antiparasitic immunity but harmful in excess, so it is important for vaccine developers to understand exactly how this arm of the immune response is regulated.

Another important avenue for genetic immunology stems from the discovery by David Modiano and colleagues that neighbouring ethnic groups in West Africa differ in their ability to make antimalarial antibodies and to control the numbers of parasites in their blood.

Has natural selection by malaria affected mankind's susceptibility to other diseases, apart from those of red blood cells? It is easy to imagine how this might affect autoimmune or inflammatory diseases, but these are not the only potential candidates since the entry of billions of malaria parasites into the blood stream disrupts oxygen supply to the tissues, energy utilization, free radical generation and many other metabolic processes.

Although there is no conclusive evidence for a relationship between malaria and common diseases of industrialized societies, many investigators believe that it is only a matter of time before such connections are discovered, particularly for conditions such as high blood pressure that are especially common in people of African origin.

The completion of genome sequences for both Homo sapiens and Plasmodium falciparum makes this a hugely exciting time to be studying the molecular basis of susceptibility to malaria.

Large epidemiological studies are underway in several different populations, including The Gambia, Kenya, Malawi, Mali, Gabon and Vietnam; and at the Wellcome Trust Centre for Human Genetics in Oxford we are working to construct the information structure to analyse extremely large amounts of data generated by mass spectrometry and other high-throughput genotyping methods, and to deliver this information straight back to the epidemiological investigators through a secure Internet interface.

One of the main challenges confronting the field of human genetic epidemiology in the postgenomic era is the need for sample sizes in the thousands, and for comparative data from genetically diverse populations.

The malaria research community is in a unique position to meet this challenge.

Professor Dominic Kwiatkowski is an MRC Research Professor at the Wellcome Trust Centre for Human Genetics, University of Oxford.

Links

Professor Dominic Kwiatkowski research page

Further information about the genome map of malaria resistance mechanisms can be found on the Gmap.net website