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

Yu Chen,Dawei Cui,Yohan Bossé,Shufa Zheng,Xiaoli Liu,Jie Zhou,Hainv Gao,Yiyin Wang,Fei Yu,Yanhui Fan,Yixin Zhu,Liang Yu,Shigui Yang,Lanjuan Li,Hin Chu,Zhongshan Cheng,Ke Hao,Cun Li,Kelvin Kai-Wang To,Pak C Sham ,Liulin Tang ,Bosco Ho Yin Wong ,Ma’en Obeidat ,C A Brandsma ,Kwok‐Yung Yuen ,You‐Qiang Song

doi:10.1038/srep08517

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).

Highlights

The fatality of avian influenza A(H7N9) infection in humans was over 30%
We demonstrated that genetic variations in lectin, galactoside-binding, soluble, 1 (LGALS1, known as Galectin 1) are contributable to the differential susceptibility to A(H7N9) influenza
The gene set analysis suggested that ECMreceptor interaction and mitogen-activated protein kinase (MAPK) signaling were the significantly enriched pathways associated with the increased susceptibility to the A(H7N9) infection. In this genome-wide association study (GWAS), we identified two polymorphic genes LGALS1 and C8B as well as two biological pathways, extracellular matrix (ECM)-receptor interaction and MAPK signaling pathway, which are significantly associated with the susceptibility to A(H7N9) infection

Summary

Introduction

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. Functional variants of LGALS1 causing the expression variations are contributable to the differential susceptibility to influenza A(H7N9). Accumulating evidence demonstrated that human genetic polymorphisms contribute to the outcome and disease severity of influenza infection. Genome-wide association study (GWAS) has been widely utilized to uncover the genetic basis of human diseases. Compared to other prevalent diseases, the relative small number of human A(H7N9) influenza cases posed a considerable difficulty to the study of genetic susceptibility to the infection. Two biological pathways, extracellular matrix (ECM)-receptor interaction and mitogen-activated protein kinase (MAPK) signaling are significantly enriched pathways associated with the susceptibility to influenza A(H7N9) infection

Methods

Results

Conclusion