Gene-Gene Interaction and Functional Impact of Polymorphisms on Innate Immune Genes in Controlling Plasmodium falciparum Blood Infection Level 英文参考文献.docVIP

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Gene-Gene Interaction and Functional Impact of Polymorphisms on Innate Immune Genes in Controlling Plasmodium falciparum Blood Infection Level 英文参考文献.doc

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Gene-Gene Interaction and Functional Impact of Polymorphisms on Innate Immune Genes in Controlling Plasmodium falciparum Blood Infection Level 英文参考文献

Gene-GeneInteractionandFunctionalImpactof PolymorphismsonInnateImmuneGenesinControlling PlasmodiumfalciparumBloodInfectionLevel MadhumitaBasu1,TaniaDas2,AlipGhosh3,SubhadipaMajumder1,ArdhenduKumarMaji4 ,Sumana DattaKanjilal5,IndranilMukhopadhyay6,SusantaRoychowdhury2,SomaBanerjee3, SanghamitraSengupta1* 1Department ofBiochemistry, UniversityofCalcutta,Kolkata,WestBengal,India, 2CancerCellBiology Division, IndianInstitute ofChemicalBiology,Kolkata,West Bengal,India,3CentreforLiverResearch,TheInstituteofPost-GraduateMedicalEducationResearch,Kolkata,WestBengal,India,4DepartmentofProtozoology,The CalcuttaSchool ofTropical Medicine,Kolkata, WestBengal, India, 5Department of Pediatric Medicine, CalcuttaNational Medical College, Kolkata, West Bengal, India, 6HumanGeneticsUnit,IndianStatisticalInstitute,Kolkata,WestBengal,India Abstract Genetic variations in toll-like receptors and cytokine genes of the innate immune pathways have been implicated in controlling parasite growth and the pathogenesis of Plasmodium falciparum mediated malaria. We previously published geneticassociationofTLR4non-synonymousandTNF-apromoterpolymorphismswithP.falciparumbloodinfectionlevel and here we extend the study considerably by (i) investigating genetic dependence of parasite-load on interleukin-12B polymorphisms,(ii)reconstructinggene-geneinteractionsamongcandidateTLRsandcytokineloci,(iii)exploringgenetic andfunctionalimpact ofepistaticmodels and(iv)providingmechanisticinsightsintofunctionality ofdisease-associated regulatorypolymorphisms.OurdatarevealedthatcarriageofAA(P=0.0001)andAC(P=0.01)genotypesofIL12B39UTR polymorphismwasassociatedwithasignificantincreaseofmeanlog-parasitemiarelativetorarehomozygousgenotypeCC. Presence of IL12B+1188 polymorphism in five of six multifactor models reinforced its strong genetic impact on malaria phenotype.Elevationofgeneticriskintwo-componentmodelscomparedtothecorrespondingsinglelocusandreduction of IL12B (2.2 fold) and lymphotoxin-a (1.7 fo