Monday March 26 2012
The actions of the rare 'flu susceptability gene' are uncertain
Scientists have discovered a “gene flaw linked to serious flu risk”, according to BBC News. The broadcaster says the mutation controls a malformed protein, which makes cells more susceptible to viral infection.
This story is based on a series of experiments that examined the influence of a gene on our susceptibility to flu. In its normal form the gene is thought to play a protective role when it comes to viral infections, although a small proportion of people may carry a mutated version of the gene. To examine the mutation’s effects researchers conducted animal experiments and genetic scans to look at the DNA of people severely affected by the flu virus in the past. The researchers found that mice lacking this gene had a much greater risk of developing severe flu than mice that had a functioning copy of the gene. Furthermore, they found that approximately 0.3% of people in the general population carry a mutated copy of the gene but that approximately 5.7% of those hospitalised with flu carried a mutated copy of the gene.
This research points to a genetic influence on flu severity. It is still at a relatively early stage, and larger studies will need to be carried out before we know precisely how this relationship works. In the longer term, this could lead to the identification of people who are likely to develop a bad case of the flu and allow them to take preventative action, such as ensuring they get the flu vaccine.
Where did the story come from?
The study was carried out by researchers from the Wellcome Trust Sanger Institutes, University College London and other institutions throughout the UK and the US. The research was supported by The Wellcome Trust and other UK funding bodies.
The study was published in peer-reviewed scientific journal Nature.
This research was covered appropriately by the media, with the BBC providing a detailed description of the study while also emphasising the early stage of the research.
What kind of research was this?
This research used a series of studies to examine the impact of a specific gene on flu susceptibility. The gene is normally responsible for producing a family of proteins called "interferon-inducible transmembrane" proteins (IFITM), which have been previously shown to keep viruses from replicating. The researchers thought that mice that did not carry a copy of the gene, and therefore did not produce the IFITM proteins, would be more likely to show signs of severe flu infection. They also thought that people with severe flu would be more likely than the general population to carry mutated versions of the gene.
The research included an animal study and a case-control study in humans. Animal studies are typically conducted early in the research process. In this case, the first study in mice allowed the researchers to examine the effects that absence of the gene had on the development of flu. It would not have been appropriate to perform this experiment in humans. Once they confirmed that the gene had a role in the susceptibility of mice to flu, they moved on to a case-control study in humans, which allowed them to examine the likelihood of people with severe flu carrying a mutated version of the gene and compare this with the likelihood among the general population. Case-control studies can show associations between two factors, but cannot confirm that one thing causes the other. In this case, the study could only show an association between carrying a mutant gene and having a severe case of flu, not that the gene made people more susceptible to the flu.
What did the research involve?
For the animal-based phase of the study the researchers took two groups of mice. The mice in one group had a copy of the IFITM gene and the mice in the other group lacked a copy of the gene. They then exposed both groups to a strain of the flu virus that is not considered to be highly virulent and does not generally produce severe disease. They compared the two groups for several outcomes, including the proportion of the mice who became infected, the proportion of the mice who survived, their weight and the amount of virus present in their lungs.
For the case-control phase of the study, the researchers sequenced the genes of 53 patients who had been hospitalised with severe H1N1 or severe seasonal flu in 2009-10. They then used an existing database, from the Wellcome Trust Case Control Consortium, to determine the proportion of the general population who carry similar IFITM mutations. By comparing these proportions, the researchers determined how much more likely the severe flu patients were to have IFITM mutations. The database included genetic sequence information from people in the UK, Netherlands and Germany.
What were the basic results?
The researchers found that, upon infection with the flu virus, mice that did not carry a copy of IFITM:
- lost more than 25% of their body weight, compared with 20% in mice with a functioning copy of the gene
- showed several signs of severe illness, such as rapid breathing and goose bumps after six days
- had 10-times higher levels of virus present in their lungs after six days, compared with the mice with the gene
- showed signs of sudden and severe pneumonia and substantial lung damage
When analysing data from the case-control study, the researchers found that patients hospitalised with severe flu were significantly more likely than the general European population to carry a specific mutation of the IFITM (5.7% of the hospitalised group compared to 0.3% of population database).
How did the researchers interpret the results?
The researchers conclude that the IFITM protein family acts as “an essential barrier to influenza A virus infection”.
This research suggests that a family of proteins has a protective role against flu infection. The mouse study indicates that when these proteins are not produced, the flu virus replicates at higher levels and can lead to more severe forms of the flu. The case-control study strengthens these findings, and indicates that there is an association between severe flu and the presence of a mutated IFITM gene in humans.
However, it is important to note several limitations to the study:
- The animal study can suggest mechanisms through which the genetic mutation may influence the development of severe flu, but the results cannot be generalised as applying to humans.
- The case-control study was small, with only 53 patients with severe flu included. Larger studies will be needed to confirm the findings.
- Case-control studies can only show an association between two factors and cannot prove that the genetic mutations cause more severe disease.
- If the genetic association can indeed cause flu susceptibility, it is unlikely that it is the sole factor governing the way people react to the flu virus. There are several known risk factors for developing severe flu (for example, being very young or old, having other medical illnesses or a weakened immune system, and socio-economic deprivation) and the manner in which these interact with genetic susceptibility is unknown.
The researchers say that IFITM is likely to be important when new flu viruses occur, as people will not yet have encountered the virus before and therefore will not yet have acquired immunity to such infections. They further say that their research shows that when IFITM proteins are not present, normally mild strains of the virus may inflict very severe symptoms. They suggest that people with IFITM mutations, and populations with a higher proportion of these mutations, may be more vulnerable to infection with the flu virus.
It is important to remember that the genetic variant seen in this research is extremely rare in Europeans. Even if it is shown to increase the odds of developing severe flu in a few people, it is unlikely to lead to severe disease on a large scale.
Analysis by Bazian