Genetic flaw opens door to deadly parasite

A new study finds that common variants in a region of the human genome that is critical to defence against infection leave people vulnerable to the most severe form of leishmaniasis, a potentially fatal parasitic disease.

The Wellcome Trust Case Control Consortium, chaired by WTCHG’s Director, Professor Peter Donnelly, worked with the LeishGEN consortium of scientists from India, Brazil, Australia and the USA on the study, published online in the journal Nature Genetics on 6 January. ‘Thanks to the hard work of clinicians and scientists in the endemic areas of India and Brazil, and the 6,000 people from those countries who have provided DNA samples, we were able to undertake the largest genetic study of this potentially fatal infectious disease’, says Professor Donnelly. 

Visceral leishmaniasis affects the internal organs, and is caused by parasites of the Leishmania genus, which are transmitted through the bite of sandflies and take up residence inside cells in the bloodstream. It is particularly prevalent in Brazil, India and South Sudan, and affects up to 400,000 people per year. Many people carry the parasite without becoming ill; however, of the one in five who do fall ill with visceral leishmaniasis, a high proportion will die.

Although it is an infectious disease, some families are more susceptible than others. The team carried out a genome-wide association study in one Brazilian and one Indian populations – a total of almost 2000 individuals. Scientists at the WTCHG led by Dr Chris Spencer looked at over half a million single-letter differences in the genetic code to see if any were associated with increased disease susceptibility. They found a group of common variants associated with visceral leishmaniasis clustered in the part of the genome known as the major histocompatibility complex (MHC), a finding later confirmed in a second Indian population. Genes in this region enable the body to distinguish between its own tissues and those of invading organisms, and to call in immune cells to destroy invaders.

Susceptible families as far apart as India and Brazil had the same pattern of association, even though the disease is caused by a different Leishmania species in each country. The result suggests that people with these genetic variants are unable to mount a strong enough immune response to the parasite to prevent the infection from taking hold. People with these common variants are not susceptible to all forms of infectious disease, and the researchers will now focus on how a small change in the genetic sequence allows the Leishmania parasite to exert its deadly effects.

Interestingly, people with the MHC variant known as DRB*15 were least likely to fall ill with the infection. This variant has been associated in other studies with increased susceptibility to multiple sclerosis, a disease in which the immune system attacks the body’s own tissues. ‘The immune system evolved to fight infection’, says Peter Donnelly. ‘But in environments where infection is less of a problem, there appear to be downsides to having such a revved-up immune system, such as an increased susceptibility to autoimmune disease.’

LeishGEN Consortium, Wellcome Trust Case Control Consortium et al, 2013. Common variants in the HLA-DRB1–HLA-DQA1 HLA class II region are associated with susceptibility to visceral leishmaniasis. 2013.  Nature Genetics, published online 6 Jan.

Peter Donnelly talks to Science in Action on the BBC World Service about genetic susceptibility to disease, incuding leishmaniasis.