Published in a leading journal this week, a large genome study of meningitis and septicaemia suggests genetic differences could be why some people are more susceptible and others naturally resistant to these diseases.
You can read about the research, led by Imperial College London and the Genome Institute of Singapore, in the online issue of Nature Genetics published on 8 August.
The international study of over 6,000 people suggests that people who develop meningitis and septicaemia caused by meningococcal bacteria have gene variants that make their immune systems unable to defend effectively against the bacteria.
Lead investigator Dr Michael Levin, a professor in the Department of Paediatrics at Imperial College London, told the press that:
“Although most of us have carried the meningitis bacteria at some point, only around one in 40,000 people develop meningococcal meningitis.”
Levin and colleagues set out to investigate why this small small group is more susceptible while the rest are immune.
“Our findings provide the strongest evidence so far that there are genetic factors that lead to people developing meningitis,” he said.
Meningitis is inflammation of the meninges, the linings that envelop and protect the brain. Various different organisms cause the disease, including viruses, bacteria and fungi.
One of the most devastating forms of the disease is the one caused by meningococcal bacteria, which kills one in ten people who fall ill.
A form of blood poisoning called meningococcal septicaemia often accompanies this form of meningitis, which strikes very quickly, with people becoming critically ill within hours. The groups most commonly affected are infants, young children, teenagers and young adults.
Co-author Dr Victoria Wright, who is also from the Department of Paediatrics at Imperial College London, co-ordinated the recruitment of participants for the study. She said:
“Meningococcal disease is a terrible illness as it strikes healthy children and adults suddenly, and can kill in a few hours.”
Improving our understanding of why some people get the disease and not others will help to identify those at risk and develop better vaccines.”
Vaccines are available for some strains of the bacteria, but not for the group B strain: Levin and colleagues hope their findings will help to find a vaccine for this strain and thereby prevent the thousands of deaths it causes across the world every year.
One of the curious things about meningococcal bacteria is that most people will carry it in their throats, on and off throughout their lives and never develop the disease. While scientists suspected that genetic factors lay behind people’s susceptibility and progression to disease, “the genes responsible for disease development are largely unknown,” wrote Levin and colleagues in their background information.
The study that Levin and colleagues performed is called a GWAS: Genome Wide Association Study, where researchers look for differences in fragments of DNA among groups of people, and try to find which differences contribute the most to a disease susceptibility or trait.
The DNA fragments are called “snips” or SNPs, which stands for single-nucleotide polymorphism. GWAS looks for variations in the “spelling” of snips: for example in one person a snip may be AAGCCTA, while the same snip in the same location on the genome of another person might differ by just one letter, for example AAGCCAT.
The researchers conducted this GWAS in two stages: in the first stage they looked for possible candidate snips that confer host susceptibility to meningococcal disease, and in the second stage they narrowed them down to the most likely ones.
In the first stage they compared the genomes of 475 people with the disease to 4,703 healthy controls and in the second stage they did two replication studies covering a total of 968 cases and 1,376 controls. The people involved in the studies were from the UK, Holland, Austria and Spain. The controls came from the Wellcome Trust Case Control Consortium.
The study was supported by the Wellcome Trust, Meningitis Research Foundation UK and the European Society for Paediatric Infectious Diseases.
Altogether, Levin and colleagues searched half a million genetic variants scattered across each participant’s genome. By the end of the search and the replication studies, they found those participants who developed meningococcal meningitis had different snips in a number of genes involved in attacking and killing invading bacteria.
The snips or gene variations they found to be most significant were in the genes for Factor H and Factor H-related proteins, which are involved in the complement system, which helps organize the immune response that recognizes and kills invading bacteria.
Factor H and Factor H-related proteins normally ensure that the immune system does not over-react and cause damage to the host’s own cells. It would appear that the meningococcal bacteria use this to their advantage and cloak themselves with host Factor H proteins so the host immune system doesn’t recognize them as foreign and leaves them alone.
The researchers said the next stage should now be to uncover the exact mechanism through which the bacteria manipulate the Factor H and Factor H-related proteins.
Sue Davie, Chief Executive of the Meningitis Trust said:
“This exciting work has thrown new light on factors that play a part in determining why some people get meningococcal disease and others do not.”
Wright praised the efforts of the participants in the study and stressed the importance of international collaboration:
“The success of the study was due to the willingness of patients and families to contribute their DNA for analysis, and it could not have been achieved without international collaboration.”
“Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease.”
Sonia Davila, Victoria J Wright, Chiea Chuen Khor, Kar Seng Sim, Alexander Binder, Willemijn B Breunis, David Inwald, Simon Nadel, Helen Betts, Enitan D Carrol, Ronald de Groot, Peter W M Hermans, Jan Hazelzet, Marieke Emonts, Chui Chin Lim, Taco W Kuijpers, Federico Martinon-Torres, Antonio Salas, Werner Zenz, Michael Levin & Martin L Hibberd for the International Meningococcal Genetics Consortium.
DOI:10.1038/ng.640
Additional sources: Imperial College London, Meningitis Trust.
Written by: Catharine Paddock, PhD