Clue to meningitis risk

"Researchers have found 'the strongest evidence so far' that genetic factors can increase the risk of a person developing meningitis," reported The Guardian . The newspaper said the discovery could help in the search for a vaccine.

This was a large, well-conducted study that compared the DNA of children who had contracted meningococcal meningitis with the DNA of healthy children. It identified several genetic variants in a region of DNA containing genes associated with a part of the immune system, including a variant in the gene that produces a protein called complement factor H (CFH). Variations in this region are linked to susceptibility to disease, and the findings may help with the development of a vaccine against type B meningococcal meningitis.

An effective vaccine against type C meningococcal meningitis is already given to children in the UK and has greatly reduced deaths from this disease in this country. Research into the development of a vaccine effective against type B meningococcal meningitis is likely to continue.

Where did the story come from?

The study was carried out by researchers from the Genome Institute of Singapore and other research institutions across the world. It was funded by the Wellcome Trust, the Agency for Science and Technology and Research of Singapore, as well as other organisations supporting the work of individual research groups. The study was published in the peer-reviewed medical journal_ Nature Genetics._

The study was reported on well by The Guardian and BBC News, with both explaining that the genetic differences between people means that some have immune systems that may be more susceptible to infection with bacterial meningitis. The reports say that these findings may help in the development of a vaccine against meningitis, although more research is needed to see whether this is feasible.

What kind of research was this?

Meningitis is a disease that results from inflammation of the lining of the brain. It can be a severe disease with a high fatality rate, usually depending on which type of infective organism the person has contracted. Meningitis is often caused by viruses or bacteria but can be caused by other microbes, including funguses. One of the most common and potentially fatal bacterial causes of meningitis is Neisseria meningitidis (meningococcal meningitis) type B, although type C caused more deaths until its vaccine was created.

This study was a genome-wide association study that looked at the DNA sequence of a large number of individuals who had meningococcal meningitis and compared this to the DNA of healthy individuals. Through this approach, the researchers were trying to identify whether there were particular genetic differences between the groups that may explain why some people are more likely to get the disease.

What did the research involve?

This research was carried out in several stages. Initially, the DNA of 475 children (average age about three years old) with meningococcal disease was examined to see how common particular genetic variations were. The variations found were then compared with the DNA from 4,703 healthy children. This identified 79 significantly different genetic variations between the groups that could be investigated further.

As is common in genome-wide association studies, the findings from an initial study are then verified in different populations. The researchers attempted to replicate their results in two further separate samples. The first was a group of 553 European children with meningococcal disease and 839 controls from the same population, which implicated 11 genetic variations that were significantly different between cases and controls. These variations were further validated in a sample of 415 children with meningococcal disease and 537 healthy individuals from Spain. The variations showing the strongest statistical significance in the three samples were discussed.

The researchers discuss how these genetic variants might affect the risk of contracting meningococcal meningitis. Discussing the biological plausibility of such findings is important.

What were the basic results?

One particular genetic variant (rs1065489) had a strong significant association with the risk of meningitis in all three of the samples. This variant lies in the gene that encodes a protein called complement factor H (CFH), which is involved in the immune response. Meningitis bacteria are known to bind to these proteins, which enables them to become hidden from the immune system.

There were a number of other variants associated with the risk of meningococcal disease, all of which were located in the “CFH cluster”, a region of genes that when deficient or mutated can result in a greater susceptibility to disease.

How did the researchers interpret the results?

The researchers conclude that their findings suggest that these variations in the CFH region play a role in determining whether colonisation with the meningococcal bacteria leads to symptomatic disease or not. They acknowledge that further DNA sequencing work is needed to identify the exact variant(s) that increase meningitis susceptibility and how it does this.

Conclusion

This is a well-conducted and well-reported genome-wide association study using recognised methods in this field of research. This study did not detect any of the genetic associations with meningococcal disease that other studies have noted, possibly because it used different methods or because these earlier studies were in smaller groups of people and so had less power to detect associations.

If this study does result in a vaccine for type B meningitis, it is likely to require further research and may be several years in the making. Positively, the researchers say that the link between the CFH variants and risk of disease seems to be “strain independent”. In other words, it exists regardless of which strain of Neisseria meningitidis (i.e. whether type B or type C) has infected the children. This is because the strain that these children had is likely to have differed across the three cohorts, as some were collected before the type C vaccine was introduced and some after. The researchers say there is potential for a meningococcal B vaccine resulting from the identification of factor H.

These findings will be of interest to geneticists and ultimately to clinicians, particularly if it aids the development of a vaccine for type B meningococcal meningitis. The vaccine for type C became available in the UK in the late 1990s and greatly reduced deaths from this disease. Any insight that can further the development of a vaccination for type B will be very welcome. It is important to note that these findings cannot be generally applied to meningitis caused by other bacteria or viruses.

Meningitis requires early recognition and urgent treatment. Symptoms include severe headache, neck stiffness, difficulty in looking at bright lights (photophobia), fever, nausea and vomiting and altered consciousness, confusion and fitting as infection progresses. In babies and young children, these characteristic signs and symptoms may not be present, and parents should be alert to either irritability or lethargy and excessive crying, fever, vomiting or poor feeding, bulging fontanelle, either a stiff or floppy body or fitting. If there is progression to septicaemia (infection of the blood), a rash which does not blanch with pressure may appear. If meningitis is suspected, seek medical attention immediately.