Identification of TMPRSS2 as a susceptibility gene for severe 2009 pandemic A(H1N1) influenza and A(H7N9) influenza

Zhongshan Cheng, Jie Zhou, Kelvin Kai Wang To, Hin Chu, Cun Li, Dong Wang, Dong Yang, Shufa Zheng, Ke Hao, Yohan Bossé, Ma'en Obeidat, Corry Anke Brandsma, You Qiang Song, Yu Chen, Bo Jian Zheng, Lanjuan Li, Kwok Yung Yuen

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1214-1221
Number of pages8
JournalJournal of Infectious Diseases
Volume212
Issue number8
DOIs
StatePublished - 15 Oct 2015

Keywords

  • A(H1N1)pdm09 influenza
  • A(H7N9) influenza
  • TMPRSS2
  • genetic variation
  • lung eQTL

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