| Background:Influenza is a global respiratory infectious disease,which is one of the major causes of global respiratory diseases and death.Virus constantly reconfigure as a new subtype,which often causes spread and epidemic in the overall population.The epidemic of influenza is related to not only the variation of the virus,but also multiple factors such as host genes,environment and social factors.Therefore,the influenza virus can cause varying degrees of clinical infections,symptoms,and prognoses.The use of single nucleotide polymorphisms,which is aimed at exploring genetic traits and studying the genetic mechanisms of infectious diseases,has become a hot topic of study today.Rare diseases are purely determined by a single gene or environmental factor.Single factor sometimes has little or even no detectable effect on disease development,gene-gene interactions can affect the progression of the disease.Objiective:By surveillancing influenza to analysis the trends of influenza in recent years,and detecting the distribution of related genes in the influenza case group and the control group,the relationship between genetic susceptibility and influenza pathogenicity is analyzed at the molecular level,further discuss the influence of the gene-gene interaction on influenza,which can provide important scientific basis for the study of the pathogenesis of influenza virus.And ultimately it will offer theoretical basis and guidelines to the prevention and control of influenza in Jiangsu Province and even the whole country.Moreover,it can provide new ideas for the early prevention of influenza,as well as the assessment of the risk of illness and the reduction of flu incidence and mortality.Methods:1.Experimental study:A case-control study was conducted.Throat swabs and bloods were collected from influenza-positive patients in Jiangsu CDC from 2015 to 2017.Positive cases were typed by fluorescent probe real-time quantitative PCR.The clinical data of all sub-type influenza patients were collected and analyzed to determine the epidemical and clinical characteristics of each subtype of flus.Polymorphisms of susceptibility gene distribution were detected by nested-PCR and gene sequencing techniques.2.Statistical Analysis and Genetic Association Study:Excel 2007 and SPSS20.0 statistical software was used to analysis data from national Influenza center.Chi-square test,Student’s t test,univariate and multivariate logistic regression analysis were used to analyze the experiment results.The Chi-Square Goodness-of-Fit Test was used to calculate whether the results of the genotype distribution of the control group were consistent with Hardy-Weinberg equilibrium(HWE).Linkage disequilibrium(LD)analysis was performed by Haploview(Ver3.2)software,multivariate logistic regression analysis and multifactor dimensionality reduction were used to analyze the interaction between genes and genes.Results:1.A(H1N1)09pdm,seasonal H3N2 and B are constantly changing from 2010 to 2017.A total of 83 patients with influenza and 118 control people were enrolled into our study.2.The relationship between genetic polymorphisms and influenza:based on the adjustment of age and gender factors,the mutation of rs4820294(G/A)in LGALS1 gene may increase the risk of influenza.Compared with the wild-type GG genotype,the risk of infection with the heterozygous mutation AA genotype is significantly increased 1.31-fold(P<0.05,OR(95%CI)=2.31(1.27,4.21)),and this locus mutation is associated with influenza B(χ~2=9.709,P<0.05).The mutation of rs2899292(A/G)in LGALS1 gene is positively correlated with the occurrence of influenza.Compared with the wild-type AA genotype,the risk of influenza infection with GG genotype is significantly increased 3.20-fold(P<0.05,OR=4.20,95%CI 1.42-12.28),and this locus variation is associated with the A(H1N1)pdm09 influenza subtype(χ~2=9.995,P<0.05).The rs1799821(A/G)in CPT2 gene may increases the risk of influenza.Compared with the wild-type AA genotype,the GG genotype significantly increases the risk of influenza infection by 13.81-fold(P<0.05,OR=14.81,95%CI 3.53-62.08),and the variation of this locus is associated with the seasonal H3N2 influenza subtype(χ~2=13.570,P<0.05).The mutation of rs5743313(C/T)in TLR3 gene is positively correlated with the occurrence of influenza.Compared with wild-type CC genotype,the risk of influenza infection of heterozygous mutation CT genotype is significantly increased 3.13-fold(P<0.05,OR=4.13,95%CI 1.62-10.56),and this locus variation is associated with influenza B(χ~2=13.254,P<0.05).In addition,rs2229291(A/G)in CPT2 gene is associated with seasonal H3N2 influenza(χ~2=4.990,P<0.05)and B-type influenza(χ~2=6.437,P<0.05).3.Relationship between genetic polymorphisms and severe influenza:rs383510 in TMPRSS2 gene(χ~2=9.706,P<0.05),rs1048479 in ST3GAL1 gene(χ~2=10.743,P<0.05)and rs5743313 in TLR3 gene(χ~2=13.386,P<0.05)are related to severe influenza,and there are significant differences in genotype distribution at each site.4.Relationship between genetic polymorphisms and their interactions with influenza:there is a two-way interaction model between rs2899292 and rs4820294 in LGALS1 gene(CVC=5/10,training-balanced accuracy is 0.653,and testing-balanced accuracy is 0.5411),which affects the risk of influenza.A three-way interaction model is shown among rs2564978in CD55 gene,rs3786054 in C1QBP gene and rs1799821 in CPT2 gene(CVC=4/10,training-balanced accuracy is 0.5097,and testing-balanced accuracy is 0.7115),which both have statistical significance(P<0.001).Conclution:1.The research indicates that rs4820294 and rs2899292 in LGALS1 gene,rs1799821 in CPT2 gene,and rs5743313 in TLR3 gene are associated with the susceptibility of influenza.2.The mutations of rs2899292 in LGALS1 gene is significantly associated with the susceptibility of influenza A(H1N1)pdm09.The mutations of rs2229291 and rs1799821 in CPT2 gene are associated with the susceptibility of seasonal H3N2 influenza.The mutations of rs4820294 in LGALS1 gene,rs2229291 in CPT2 gene,and rs5743313 in TLR3 gene are related to influenza B.3.The rs383510 in TMPRSS2 gene,rs1048479 in ST3GAL1 gene,and rs5743313 in TLR3 gene are associated with severe influenza.4.The two-way interaction model between rs4820294 and rs2899292 in LGALS1 gene and the three-way interaction model among rs2564978 in CD55 gene,rs3786054 in C1QBP gene and rs1799821 in CPT2 gene may affect the risk of influenza.These results still need to be repeatedly verified in Chinese who have the characteristics of large-scale and multi-site to better explain biological functions. |
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