Researchers led by St. Jude Children's Research Hospital have identified a genetic variation associated with influenza severity and the supply of killer T cells that help patients fight the infection.
Researchers have discovered an inherited genetic variation that may help identify patients at elevated risk for severe, potentially fatal influenza infections. The scientists have also linked the gene variant to a mechanism that explains the elevated risk and offers clues about the broader anti–viral immune response.

The research appeared in the journal Nature Medicine.

Researchers screened 393 flu patients ranging from infants to 70 years old. Patients with a particular inherited variation in the gene IFITM3 were more than twice as likely to develop severe, life–threatening flu symptoms as those who carried the protective version of the gene.

Working at the molecular level, the investigators showed how expression of the IFITM3 protein was reduced in killer T cells of patients with the high–risk variant compared to other patients. Researchers also found more killer T cells in the upper airways of flu patients with the protective variant compared to other patients.

"A genetic marker of flu risk could make a life–saving difference, particularly during severe flu outbreaks, by helping prioritize high–risk patients for vaccination, drug therapy and other interventions," said corresponding author Paul Thomas, PhD, an associate member of the St. Jude Department of Immunology. "These results raise hopes that this newly identified IFITM3 variant might provide such a marker."

IFITM3 is an anti–viral protein that helps to block flu infection of lung cells and to promote survival of the killer T cells that help clear flu infection in the airways. Previous research from other scientists had reported an association between another IFITM3 variant (rs12252) and flu severity in Han Chinese patients. The underlying mechanism has remained unclear, and the rs12252 variant is rare in individuals of European ancestry.

Thomas and his colleagues began this study by searching for other possible IFITM3 variants that correlated with gene expression, levels of the IFITM3 proteins and were common in flu patients in the U.S. The search led to an IFITM3 variant known as rs34481144.

Researchers screened three different groups of U.S. flu patients and found those with the high–risk version of IFITM3 rs34481144 were likely to become infected with flu more rapidly and to develop more severe symptoms than those with another variant. For example, researchers checked 86 children and adults in Memphis with confirmed flu infections and found two–thirds of patients with the most severe symptoms carried at least one copy of the newly identified high–risk IFITM3 variant. The high–risk variant was found in just 32 percent of patients with milder symptoms.

Researchers also found an association between the newly identified high–risk variant and severe and fatal flu infections in 265 critically ill pediatric flu patients hospitalized in one of 31 intensive care units nationwide. The patients did not have health problems that put them at high risk for severe flu. Of the 17 patients in this group who died from the infection, 14 carried at least one copy of the newly identified high–risk variant. "When we looked at patients of European descent who died, they all carried at least one copy of the high–risk variant," Thomas said.

Further study revealed how binding differed between the high–risk and protective variants. Those differences led to lower levels of the IFITM3 protein in individuals with two copies of the high–risk gene variant compared to other patients, researchers said. The Memphis flu patients also had fewer of the killer T cells in their upper airways.