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25-03-2012 | Genetics | Article

Human gene variant can transform mild flu into serious disease


Free abstract

MedWire News: People with a specific variant of the interferon-inducible transmembrane 3 gene (IFITM3) are more likely to be hospitalized with seasonal or pandemic influenza than noncarriers, suggest study results published in Nature.

Recent research has shown that IFITM3 and related proteins are powerful restrictors of viral replication in vitro, suggesting that they are critical for stimulating effective resistance to a variety of pathogenic viruses including influenza.

"Since IFITM3 appears to be a first line defender against infection, our efforts suggest that individuals and populations with less IFITM3 activity may be at increased risk during a pandemic," said study author Abraham Brass (Ragon Institute of Massachusetts General Hospital, Charlestown, USA) in a press statement.

Brass, Paul Kellam (Wellcome Trust Sanger Institute, Hinxton, UK), and colleagues investigated the role of IFITM3 in regulation of influenza infection in mice and humans.

They found that functional IFITM3 is essential for defense against the influenza A virus in vivo, as mice genetically engineered to have a defective copy of Ifitm3 developed fulminant viral pneumonia on exposure to the normally low-pathogenicity virus.

To test the role of IFTIM3 in humans, the researchers sequenced IFITM3 and searched for function changing single nucleotide polymorphisms (SNPs) in 53 patients hospitalized with seasonal or pandemic H1N1 influenza in 2009, 24 of whom were admitted to an intensive care unit.

The team found that genotypes for the SNP rs12252 (C/T), which alters a splice acceptor site, differed significantly between patients hospitalized for flu and ethnically matched European controls. The hospitalized patients were significantly more likely to be carriers or homozygotes of the minor C allele than controls, at 7.5% and 5.7% versus 6.7% and 0.3%, respectively.

The team believes that the C allele of rs12252 "may be associated with the IFITM3 splice variant (ENST00000526811), which encodes an IFITM3 protein lacking the first 21 amino acids due to the use of an alternative start codon."

"Collectively, these data reveal that the action of a single antiviral protein, IFITM3, can profoundly alter the course of the flu and potentially other viruses in both human and mouse," explained Kellam.

"To fully understand how both the protein and gene control our susceptibility to viral infections, we need to study the mechanisms of the gene variant more closely."

He concluded: "Our research is important for people who have this variant as we predict their immune defences could be weakened to some virus infections. Ultimately as we learn more about the genetics of susceptibility to viruses, then people can take informed precautions, such as vaccination to prevent infection."

By Helen Albert

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