title: Identification of TMPRSS2 as a Susceptibility Gene for Severe 2009 Pandemic A(H1N1) Influenza and A(H7N9) Influenza.
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.
authors.affiliation: Department of Microbiology.
authors.forename: Zhongshan
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Department of Microbiology Research Centre of Infection and Immunology State Key Laboratory of Emerging Infectious Diseases.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Microbiology Research Centre of Infection and Immunology State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for Infection.
authors.forename: Kelvin Kai-Wang
authors.initials: KK
authors.lastname: To
authors.affiliation: Department of Microbiology Research Centre of Infection and Immunology State Key Laboratory of Emerging Infectious Diseases.
authors.forename: Hin
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Microbiology.
authors.forename: Cun
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Microbiology.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Microbiology.
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, China.
authors.forename: Shufa
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: Department of Molecular Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, Canada.
authors.forename: Ma'en
authors.initials: M
authors.lastname: Obeidat
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, The Netherlands.
authors.forename: Corry-Anke
authors.initials: CA
authors.lastname: Brandsma
authors.affiliation: Department of Biochemistry, The University of Hong Kong, Pok Fu Lam.
authors.forename: You-Qiang
authors.initials: YQ
authors.lastname: Song
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Microbiology Research Centre of Infection and Immunology State Key Laboratory of Emerging Infectious Diseases.
authors.forename: Bo-Jian
authors.initials: BJ
authors.lastname: Zheng
authors.affiliation: State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, China.
authors.forename: Lanjuan
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Microbiology Research Centre of Infection and Immunology State Key Laboratory of Emerging Infectious Diseases Carol Yu Centre for Infection.
authors.forename: Kwok-Yung
authors.initials: KY
authors.lastname: Yuen
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics*; D064766:Influenza A Virus, H7N9 Subtype / Q000235:genetics*; D007251:Influenza, Human / Q000821:virology*; D008168:Lung / Q000821:virology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012697:Serine Endopeptidases / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human
keywords: A(H1N1)pdm09 influenza; A(H7N9) influenza; TMPRSS2; genetic variation; lung eQTL