A mutated gene that more than doubles the risk of dying from flu has been discovered in a breakthrough that could save thousands of lives.
It could help identify those most vulnerable to the potentially fatal seasonal infection - ensuring they get vaccinated.
The protein is an inherited version of a gene known as IFITM3 - found in the immune system's killer T cells that combat infection.
A study of almost 400 people - ranging in age from infants to 70 years old - found carriers were more than twice as likely to develop life-threatening flu symptoms.
Immunologist Dr Paul Thomas, of St Jude Children's Research Hospital in Memphis, said: "A genetic marker of flu risk could make a life-saving difference, particularly during severe flu outbreaks, by helping prioritise high-risk patients for vaccination, drug therapy and other interventions.
"These results raise hopes this newly identified IFITM3 variant might provide such a marker."
In some years flu causes the deaths of over 10,000 people in the UK - mainly among the elderly.
Pensioners most at risk
Research has shown pensioners are more likely to die of flu or pneumonia.
Now the mutation may help identify patients at elevated risk for severe, potentially fatal symptoms.
The scientists have also linked it to a mechanism that explains the cause - and offers clues about the broader anti-viral immune response.
The study published in Nature Medicine screened 393 flu patients and found life-threatening symptoms were much more common in those with the IFITM3 variant compared to the protective version.
Working at the molecular level the researchers showed the mutation reduced expression of the IFITM3 protein in killer T cells.
They also found more killer T cells - which help patients fight the infection - in the nose and throat of those with the protective variant.
The IFITM3 gene produces an anti-viral protein that helps block flu in lung cells and boosts killer T cells that clear infection in the airways.
An earlier study of Chinese patients by another team found a link between another IFITM3 variant (rs12252) and flu severity.
But the underlying mechanism has remained unclear and the rs12252 mutation is rare in individuals of European ancestry.
So Dr Thomas and colleagues looked for other IFITM3 mutations in US patients and found one known as rs34481144.
Those carriers were likely to become infected with flu more rapidly and to develop more severe symptoms.
Checks on flu infections in 86 children and adults in Memphis found two-thirds of those with the most severe symptoms carried at least one copy of the high-risk IFITM3 variant - compared to only 32 percent of those with milder symptoms.
It was also linked to severe and fatal flu infections in 265 critically ill paediatric patients who did not have any other health problems. Of the 17 who died 14 carried at least one copy of the mutation.
Dr Thomas said: "When we looked at patients of European descent who died they all carried at least one copy of the high-risk variant."
It's found in the region of IFITM3 linked to a master regulator called CTCF which can suppress gene activity.
Dr Thomas said: "While this research focused on flu infections, the mechanism we identified has implications for regulating many genes involved in anti-viral activity.
"CTCF has gained prominence in recent years as a master regulator of genomic organisation.
"Evidence in this study suggests the high-risk variant we identified may be part of a larger network of CTCF binding sites involved in regulation in other genes with anti-viral activity."
Flu epidemics can kill thousands or even millions of people. The 1918 flu epidemic is estimated to have affected half the world's population - and killed 40-50 million people worldwide.
In the UK the annual flu season runs from about October to March or April. Most cases of flu occur between December and February.