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Functional variants regulating LGALS1 (Galectin 1) expression affect human susceptibility to influenza A(H7N9).

ABSTRACT: The fatality of avian influenza A(H7N9) infection in humans was over 30%. To identify human genetic susceptibility to A(H7N9) infection, we performed a genome-wide association study (GWAS) involving 102 A(H7N9) patients and 106 heavily-exposed healthy poultry workers, a sample size critically restricted by the small number of human A(H7N9) cases. To tackle the stringent significance cutoff of GWAS, we utilized an artificial imputation program SnipSnip to improve the association signals. In single-SNP analysis, one of the top SNPs was rs13057866 of LGALS1. The artificial imputation (AI) identified three non-genotyped causal variants, which can be represented by three anchor/partner SNP pairs rs13057866/rs9622682 (AI P = 1.81 × 10(-7)), rs4820294/rs2899292 (2.13 × 10(-7)) and rs62236673/rs2899292 (4.25 × 10(-7)) respectively. Haplotype analysis of rs4820294 and rs2899292 could simulate the signal of a causal variant. The rs4820294/rs2899292 haplotype GG, in association with protection from A(H7N9) infection (OR = 0.26, P = 5.92 × 10(-7)) correlated to significantly higher levels of LGALS1 mRNA (P = 0.050) and protein expression (P = 0.025) in lymphoblast cell lines. Additionally, rs4820294 was mapped as an eQTL in human primary monocytes and lung tissues. In conclusion, functional variants of LGALS1 causing the expression variations are contributable to the differential susceptibility to influenza A(H7N9).

SUBMITTER: Chen Y

PROVIDER: S-EPMC4649671 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Functional variants regulating LGALS1 (Galectin 1) expression affect human susceptibility to influenza A(H7N9).

Chen Yu Y Zhou Jie J Cheng Zhongshan Z Yang Shigui S Chu Hin H Fan Yanhui Y Li Cun C Wong Bosco Ho-Yin BH Zheng Shufa S Zhu Yixin Y Yu Fei F Wang Yiyin Y Liu Xiaoli X Gao Hainv H Yu Liang L Tang Linglin L Cui Dawei D Hao Ke K Bossé Yohan Y Obeidat Ma'en M Brandsma Corry-Anke CA Song You-Qiang YQ To Kelvin Kai-Wang KK Sham Pak Chung PC Yuen Kwok-Yung KY Li Lanjuan L

Scientific reports 20150217

The fatality of avian influenza A(H7N9) infection in humans was over 30%. To identify human genetic susceptibility to A(H7N9) infection, we performed a genome-wide association study (GWAS) involving 102 A(H7N9) patients and 106 heavily-exposed healthy poultry workers, a sample size critically restricted by the small number of human A(H7N9) cases. To tackle the stringent significance cutoff of GWAS, we utilized an artificial imputation program SnipSnip to improve the association signals. In singl ...[more]

PMID: 25687228

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Project description:BackgroundBoth seasonal and novel avian influenza viruses can result in severe infections requiring hospitalization. Anti-influenza antibodies (Abs) with Fc-mediated effector functions, such as Ab-dependent cellular cytotoxicity (ADCC), are of growing interest in control of influenza but have not previously been studied during severe human infections. As such, the objective of this study was to examine Fc-mediated Ab functions in humans hospitalized with influenza infection.MethodsSerum Ab response was studied in subjects hospitalized with either pandemic H7N9 avian influenza virus in China (n = 18) or circulating seasonal influenza viruses in Melbourne, Australia (n = 16). Recombinant soluble Fc receptor dimer ELISAs, natural killer (NK) cell activation assays, and Ab-dependent killing assays with influenza-infected target cells were used to assess the Fc functionality of anti-influenza hemagglutinin (HA) Abs during severe human influenza infection.ResultsWe found that the peak generation of Fc functional HA Abs preceded that of neutralizing Abs for both severe H7N9 and seasonal influenza infections. Subjects who succumbed to complications of H7N9 infection demonstrated reduced HA-specific Fc receptor-binding Abs (in magnitude and breadth) immediately prior to death compared with those who survived. Subjects who recovered from H7N9 and severe seasonal influenza infections demonstrated increased Fc receptor-binding Abs not only against the homologous infecting strain but against HAs from different influenza A subtypes.ConclusionCollectively, survivors of severe influenza infection rapidly generate a functional Ab response capable of mediating ADCC against divergent influenza viruses. Broadly binding HA Abs with Fc-mediated functions may be a useful component of protective immunity to severe influenza infection.FundingThe National Health and Medical Research Council ([NHMRC] grants 1023294, 1041832, and 1071916), the Australian Department of Health, and the joint University of Melbourne/Fudan University International Research and Research Training Fund provided funding for this study.

Dataset Information

Functional variants regulating LGALS1 (Galectin 1) expression affect human susceptibility to influenza A(H7N9).

Publications

Functional variants regulating LGALS1 (Galectin 1) expression affect human susceptibility to influenza A(H7N9).

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