Identification of TMPRSS2 as a Susceptibility Gene for Severe 2009 Pandemic A(H1N1) Influenza and A(H7N9) Influenza

J Infect Dis. 2015 Oct 15;212(8):1214-21. doi: 10.1093/infdis/jiv246. Epub 2015 Apr 22.


The genetic predisposition to severe A(H1N1)2009 (A[H1N1]pdm09) influenza was evaluated in 409 patients, including 162 cases with severe infection and 247 controls with mild infection. We prioritized candidate variants based on the result of a pilot genome-wide association study and a lung expression quantitative trait locus data set. The GG genotype of rs2070788, a higher-expression variant of TMPRSS2, was a risk variant (odds ratio, 2.11; 95% confidence interval, 1.18-3.77; P = .01) to severe A(H1N1)pdm09 influenza. A potentially functional single-nucleotide polymorphism, rs383510, accommodated in a putative regulatory region was identified to tag rs2070788. Luciferase assay results showed the putative regulatory region was a functional element, in which rs383510 regulated TMPRSS2 expression in a genotype-specific manner. Notably, rs2070788 and rs383510 were significantly associated with the susceptibility to A(H7N9) influenza in 102 patients with A(H7N9) influenza and 106 healthy controls. Therefore, we demonstrate that genetic variants with higher TMPRSS2 expression confer higher risk to severe A(H1N1)pdm09 influenza. The same variants also increase susceptibility to human A(H7N9) influenza.

Keywords: A(H1N1)pdm09 influenza; A(H7N9) influenza; TMPRSS2; genetic variation; lung eQTL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Cohort Studies
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Influenza A Virus, H1N1 Subtype / genetics*
  • Influenza A Virus, H7N9 Subtype / genetics*
  • Influenza, Human / virology*
  • Lung / virology
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Quantitative Trait Loci
  • Serine Endopeptidases / genetics*
  • Severity of Illness Index


  • Serine Endopeptidases
  • TMPRSS2 protein, human