期刊
JOURNAL OF INFECTIOUS DISEASES
卷 212, 期 8, 页码 1214-1221出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiv246
关键词
TMPRSS2; genetic variation; lung eQTL; A(H1N1)pdm09 influenza; A(H7N9) influenza
资金
- Providence Foundation Limited
- Health and Medical Research Fund, Food and Health Bureau, Hong Kong Special Administrative Region [12111412, RRG-05, HKM-15-M03]
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.
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